AU2006258046A1

AU2006258046A1 - Synergistic modulation of FLT3 kinase using aminoquinoline and aminoquinazoline kinase modulators

Info

Publication number: AU2006258046A1
Application number: AU2006258046A
Authority: AU
Inventors: Christian Andrew Baumann; Michael David Gaul
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2005-06-10
Filing date: 2006-06-07
Publication date: 2006-12-21
Also published as: WO2006135636A2; CN101242838A; BRPI0611923A2; KR20080019695A; CA2611584A1; JP2008545785A; WO2006135636A3; EP1893206A2; US20060281771A1

Description

WO 2006/135636 PCT/US2006/022142 TITLE OF THE INVENTION SYNERGISTIC MODULATION OF FLT3 KINASE USING AMINOQUINOLINE AND AMINOQUINAZOLINE KINASE MODULATORS 5 CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application for Patent No. 60/689,721, filed June 10, 2005, the entire disclosure of which is hereby incorporated 10 in its entirely. FIELD OF THE INVENTION The present invention relates to the treatment of a cell proliferative disorder or 15 disorders related to FLT3 using a farnesyl transferase inhibitor in combination with an inhibitor of FLT3 tyrosine kinase. BACKGROUND OF THE INVENTION 20 The fins-like tyrosine kinase 3 (FLT3) ligand (FLT3L) is one of the cytokines that affects the development of multiple hematopoietic lineages. These effects occur through the binding of FLT3L to the FLT3 receptor, also referred to as fetal-liver kinase-2 (flk-2) and STK-1, a receptor tyrosine kinase (RTK) expressed on hematopoietic stem and progenitor cells. The FLT3 gene encodes a membrane 25 spanning class III RTK that plays an important role in proliferation, differentiation and apoptosis of cells during normal hematopoiesis. The FLT3 gene is mainly expressed by early myeloid and lymphoid progenitor cells. See McKenna, Hilary J. et al. Mice lacking fit3 ligand have deficient hematopoiesis affecting hematopoietic progenitor-cellsdendritic-cells,aid n-itiffl-kiillEr cellff. BlKo-d. Jiin 2000, 95:3489- 30 3497; Drexler, H. G. and H. Quentmeier (2004). "FLT3: receptor and ligand." Growth Factors 22(2): 71-3.

WO 2006/135636 PCT/US2006/022142 The ligand for FLT3 is expressed by the marrow stromal cells and other cells and synergizes with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells. 5 Hematopoietic disorders are pre-malignant disorders of these systems and include, for instance, the myeloproliferative disorders, such as thrombocythemia, essential thrombocytosis (ET), angiogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (IMF), polycythemia vera (PV), the cytopenias, and pre-malignant myelodysplastic 10 syndromes. See Stirewalt, D. L. and J. P. Radich (2003). "The role of FLT3 in haematopoietic malignancies." Nat Rev Cancer 3(9): 650-65; Scheijen, B. and J. D. Griffin (2002). "Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease." Oncogene 21(21): 3314-33. 15 Hematological malignancies are cancers of the body's blood forming and immune systems, the bone marrow and lymphatic tissues. Whereas in normal bone marrow, FLT3 expression is restricted to early progenitor cells, in hematological malignancies, FLT3 is expressed at high levels or FLT3 mutations cause an uncontrolled induction of the FLT3 receptor and downstream molecular pathway, possibly Ras activation. 20 Hematological malignancies include leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma-- for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute 25 undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders mixed) , multiple-myeloma, (MM)-and-myeloid-sarcoma-See Kot-idif,P. D_,R.E. 30 Gale, et al. (2003). "Flt3 mutations and leukaemia." Br J Haematol 122(4): 523-38. Myeloid sarcoma is also associated with FLT3 mutations. See Ansari-Lari, Ali et al. FLT3 mutations in myeloid sarcoma. British Journal of Haematology. 2004 Sep. 126(6):785-91. 2 WO 2006/135636 PCT/US2006/022142 Acute Myelogenous Leukemia (AML) is the most prevalent form of adult leukemia and represents 15-20% of childhood leukemias. In 2002, in the United States, approximately 11,000 new cases of AML were diagnosed and an estimated 8,000 5 patients died from AML. See National Cancer Institute SEER database http://seer.cancer.gov/. Although diagnosis for AML is traditionally based on histological techniques and blood leukocyte count, recent advances in cytogenetic and genetic analysis have revealed that AML is a mixture of distinct diseases that differ in their genetic abnormalities, clinical features and response to therapy. Recent efforts 10 have begun to tailor chemotherapy to the different sub-types of AML (subtypes are based on cytogenetic analysis and immunohistochemrnical analysis for disease associated protein expression) with some success. Treatment of AML typically occurs in two phases: induction and post-induction therapy. Induction therapy typically consists of three doses of an anthracycline such as daunorubicin followed by 15 i.v. bolus infusion of the cytotoxic cytarabine for 7- 10 days. This regime is effective at inducing remission in 70-80% of patient < 60 years of age and ~50% of patients > 60. See Burnett, A. K. (2002). "Acute myeloid leukemia: treatment of adults under 60 years." Rev Clin Exp Hematol 6(1): 26-45; Buchner T., W. Hiddemann, et al. (2002). "Acute myeloid leukemia: treatment over 60." Rev Clin Exp Hematol. 6(1):46-59. 20 After remission induction there are several post-induction options including an additional cycle of chemotherapy or bone marrow transplantation. Post-induction treatment choice and success depends on the patient's age and AML sub-type. Despite the advances in diagnosis and treatment of AML over the last decade, the 5 year disease free survival for patients under 65 is only 40% and the 5 year disease free 25 survival of patients over 65 is less than 10% percent. Thus, there remains a significant unmet clinical need for AML particularly in patients over 65. With the increased knowledge of the mechanisms of the different sub-types of AML new tailored treatments for the disease are beginning to immerge with some promising results. 30 One recent success in relapse and refractory AML treatment is the development and use of farnesyl transferase inhibitors (FTI) for post-induction treatment. Farnesyl transferase inhibitors are a potent and selective class of inhibitors of intracellular 3 WO 2006/135636 PCT/US2006/022142 farnesyl protein transferase (FPT). FPT catalyses the lipid modification of a host of intracellular proteins, including the small GTPases of the Ras and Rho family and lamin proteins, to direct their localization to the plasma membrane or membrane compartments within the cell. 5 FTIs were originally developed to prevent post-translational farnesylation and activation of Ras oncoproteins (Prendergast G.C. and Rane, N. (2001) "Farnesyl Transferase Inhibtors: Mechanism and Applications" Expert Opin Investig Drugs. 10(12):2105-16). Recent studies also demonstrate FTI induced inhibition of Nf-KB 10 activation leading to increased sensitivity to induction of apoptosis and downregulation of inflammatory gene expression through suppression of Ras dependent Nf- KBd3 activation. See Takada, Y., et al. (2004). "Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kappaB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-kappaB 15 regulated gene expression and up-regulation of apoptosis."J Biol Chem 279, 26287 99. Of particular interest for oncology, FTI inhibition of the oncogenes of the Ras and Rho family leads to growth arrest and apoptosis of tumor cells both in vitro and in 20 vivo. See Haluska P., G.K. Dy, A.A. Adjei. (2002) "Farnesyl transferase inhibitors as anticancer agents." Eur J Cancer. 38(13):1685-700. From a clinical perspective, myeloid malignancies, particularly AML, represent a significant opportunity for FTI therapy. 25 As discussed earlier, AML is a disease with very low long-term survival and an elevated rate of chemotherapy-induced toxicity and resistance (particularly in patients > 60 years of age). Additionally, the mechanism of proliferation of AML cells relies on the small GTPases of the Ras and Rho family. With the plethora of pre-clinical data supporting-the-efficacy-of--FTIs-in-AML-treatn-int,-ee a cliiii t alFrials were 30 initiated with an FTI including; Tipifarnib (ZarnestraTM, Johnson and Johnson), BMS 214662, CP-60974 (Pfizer) and Sch-6636 (lonafarnib, Schering-Plough). 4 WO 2006/135636 PCT/US2006/022142 ZARNESTRA® (also known as R115777 or Tipifarnib) is the most advanced and promising of the FTI class of compounds. In clinical studies of patients with relapsed and refractory AML, Tipifarnib treatment resulted in a ~30% response rate with 2 patients achieving complete remission. See Lancet J.E., J.D. Rosenblatt, J.E. Karp. 5 (2003) "Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias." Semin Hematol. 39(3 Suppl 2):31-5. These responses occurred independently of the patients Ras mutational status, as none of the patients in the trial had the Ras mutations that are sometimes seen in AML patients. However, there was a direct correlation of patient responses to their level of 10 MAPkinase activation (a downstream target of both Ras and Rho protein activity) at the onset of treatment, suggesting that the activity of the Ras/MAPkinase pathway, activated by other mechanisms may be a good predictor of patient responses. See Lancet J.E., J.D. Rosenblatt, J. E. Karp. (2003) "Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias." 15 Semin Hematol. 39(3 Suppl 2): 31-5. Additionally, a recent multicenter Phase II trial in patients with relapsed AML demonstrated complete responses (bone marrow blasts <5%) in 17 of 50 patients and a >50% reduction in bone marrow blasts in 31 of 50 patients. Reviewed in Gotlib, J (2005) "Farnesyltransferase inhibitor therapy in acute myelogenous leukemia." Curr. Hematol. Rep.;4(1):77-84. Preliminary analysis of 20 genes regulated by the FTI treatment in responders in that trial also demonstrated an effect on proteins in the MAPKinase pathway. This promising result has experts in the field anticipating the use of Tipifarnib in the clinic in the near future. Recently, another target for the treatment of AML, and a subset of patients with MDS 25 and ALL, has emerged. The receptor tyrosine kinase, FLT3 and mutations of FLT3, have been identified as key player in the progression of AML. A summary of the many studies linking FLT3 activity to disease have been extensively reviewed by Gilliland, D. G. and J. D. Griffin (2002). "The roles of FLT3 in hematopoiesis and leukemia.- Bloodi00(5): 1532-42,-and-Stirewalt-D. LT-and-J.P.- Ra-dk-if(2003). "iThe 30 role of FLT3 in haematopoietic malignancies." Nat Rev Cancer 3(9): 650-65. Greater than 90% of patients with AML have FLT3 expression in blast cells. It is now known that roughly 30-40% of patients with AML have an activating mutation of FLT3, making FLT3 mutations the most common mutation in patients with AML. There are 5 WO 2006/135636 PCT/US2006/022142 two known types of activating mutations of FLT3. One is a duplication of 4-40 amino acids in the juxtamembrane region (ITD mutation) of the receptor (25-30% of patients) and the other is a point mutation in the kinase domain (5-7% of patients). These receptor mutations cause constituitive activation of multiple signal transduction 5 pathways including Ras/MAPkinase, PI3kinase/AKT, and the STAT pathways. Additionally, the FLT31TD mutation also has been shown to decrease the differentiation of early myeloid cells. More significantly, patients with the ITD mutation have decreased rates of remission induction, decreased remission times, and poorer overall prognosis. FLT3ITD mutations have also been found in ALL with the 10 MLL gene rearrangement and in a sub-population of MDS patients. The presence of the FLT3ITD mutation in MDS and ALL is also correlated with accelerated disease progression and poorer prognosis in these patients. See Shih L. Y. et al., (2004) "Internal tandem duplication of fms-like tyrosine kinase 3 is associated with poor outcome in patients with myelodysplastic syndrome." Cancer, 101; 989-98; and 15 Armstrong, S.A. et al., (2004) "FLT3 mutations in childhood acute lymphoblastic leukemia." Blood. 103: 3544-6. To date, there is no strong evidence that suggests either the kinase domain point mutations or the over expressed wild-type receptor is causative of disease, however, FLT3 expression may contribute to the progression of the disease. This building pre-clinical and clinical evidence has led to the 20 development of a number of FLT3 inhibitors which are currently being evaluated in the pre-clinical and clinical setting. An emerging strategy for the treatment of AML is the combination of target directed therapeutic agents together or with conventional cytotoxic agents during induction 25 and/or post-induction therapy. Recent proof of concept data has been published that demonstrate the combination of the cytotoxic agents (such as cytarabine or daunorubicin) and FLT3 inhibitors inhibit the growth of AML cells expressing FLT3ITD. See Levis, M., R. Pham, et al. (2004). "In vitro studies of a FLT3 inhibitor combined-with chemotherapy:- sequence-of-administration-is-importan-t t0-aci-eve 30 synergistic cytotoxic effects." Blood 104(4): 1145-50, and Yee KW, Schittenhelm M, O'Farrell AM, Town AR, McGreevey L, Bainbridge T, Cherrington JM, Heinrich MC. (2004) "Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT31TD-positive leukemic cells." Blood. 104(13):4202-9. 6 WO 2006/135636 PCT/US2006/022142 Accordingly, the present invention provides a synergistic method of treatment comprising co-administration (simultaneous or sequential) of a novel FLT3 kinase inhibitor described herein and a farnesyl transferase inhibitor for the treatment of 5 FLT3 expressing cell proliferative disorders. A variety of FTase inhibitors are currently known. FTIs appropriate for use in the present invention are the following: WO-97/21701 and U.S. Patent No. 6,037,350, which are incorporated herein in their entirety, describe the preparation, formulation 10 and pharmaceutical properties of certain farnesyl transferase inhibiting (imidazoly-5 yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (III) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by R3 NR3 R16 R 4 N HN ,R5 R 2g H.. R 2 1 19

R

18 I Rg -R6 Rg -R6 x N R1 R7 N i Ry 18 R7 RI (I) (II) R3 R16

R

4 R2 I=N--R R2 HN Rg -R6 R17R18 R7 (i0 15 theph1rmaceutically acceptable-acid-or-base-addition-salts-and-the-stee6chiicaly isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; 7 WO 2006/135636 PCT/US2006/022142

R

1 is hydrogen, Ci1-12alkyl, Arl 1 , Ar 2 C 1-6alkyl, quinolinylCi1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C 1-6alkyl)aminoC 1-6alkyl, aminoC 1-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(0)2-R 9 , 5 wherein Alk 1 is C1-6alkanediyl,

R

9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C 1-8alkylamino substituted with Ci1-6alkyloxycarbonyl;

R

2 , R 3 and R 16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, 10 aminoCl-6alkyloxy, mono- or di(C1-6alkyl)aminoCl-6alkyloxy, Ar 1 , Ar 2 C1-6alkyl, Ar 2 oxy, Ar 2 C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4 dimethyloxazolyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical 15 of formula -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), 20 -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6);

R

4 and R 5 each independently are hydrogen, halo, Ar 1 , C1-6alkyl, hydroxyCl 6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C 1-6alkylS(O)C 1-6alkyl or C 1 25 6alkylS (O)2C 1-6alkyl;

R

6 -atd-R7--ah-idependently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar 2 oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or when on adjacent positions R 6 and R 7 taken together may form a bivalent radical of formula 8 WO 2006/135636 PCT/US2006/022142 -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2);

R

8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, 5 carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC 1-6alkyl, or a radical of formula -O-R10 (b-1), -S-R10 (b-2), 10 -N-R 1 1

R

12 (b-3), wherein R 10 is hydrogen, C1-6alkyl, Cl-6alkylcarbonyl, Ar 1 , Ar 2 Cl-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk 2 OR 13 or -Alk 2

-NR

14

R

15 ;

R

11 is hydrogen, C1-l2alkyl, Ar 1 or Ar 2 C1-6alkyl; 15 R 12 is hydrogen, C1-6alkyl, C1-16alkylcarbonyl, C1-6alkyloxycarbonyl, C 1-6alkylaminocarbonyl, Ar 1 , Ar 2 C 1-6alkyl, CI -6alkylcarbonylC1-6alkyl, a natural amino acid, Ar 1 carbonyl, Ar 2 C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1 6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, 20 di(C 1-6alkyl)aminoC 1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical of formula -Alk 2

-OR

13 or Alk 2

-NR

14

R

15 ; wherein Alk 2 is C1-6alkanediyl;

R

13 is hydrogen, C1-6alkyl, Cl-6alkylcarbonyl, 25 -hydroxyCler-6alkyl, -AFY 1 -6Ar 2 C i-6alkyl;

R

14 is hydrogen, C1-6alkyl, Arl or Ar 2 C1-6alkyl;

R

15 is hydrogen, C1-6alkyl, Cl-6alkylcarbonyl, Ar 1 or Ar 2 C1-6alkyl; 9 WO 2006/135636 PCT/US2006/022142

R

17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Arl;

R

18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;

R

19 is hydrogen or C1-6alkyl; Ar 1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy 5 or halo; and Ar 2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo. WO-97/16443 and U.S. Patent No. 5,968,952, which are incorporated herein in their 10 entirety, describe the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by . g 3 R3 X R R2 R R

R

3 R

R

10 R -o R X N R6 N R 7 1 R"

RR

7 R (IV) (V 15 R 2 riR 4-W R 5R R6 R" O (VI) 10 WO 2006/135636 PCT/US2006/022142 the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; 5 R 1 is hydrogen, C1-12alkyl, Ar 1 , Ar 2 C1-6alkyl, quinolinylC1.-6alkyl, pyridylC1-6alkyl, hydroxyC 1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C 1-6alkyl)aminoC 1-6alkyl, aminoC1-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(0)2-R 9 , wherein Alk 1 is C1-6alkanediyl, 10 R 9 is hydroxy, C1-6alkyl, Cl-6alkyloxy, amino, C1-8alkylamino or Cl-8alkylamino substituted with Cl-6alkyloxycarbonyl;

R

2 and R 3 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C 1-6alkyloxy, hydroxyC 1-6alkyloxy, C 1-6alkyloxyC 1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar 1 , 15 Ar 2 C 1 -6alkyl, Ar 2 oxy, Ar 2 C 1-6alkyloxy, hydroxycarbonyl, C -6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1), 20 -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); 25 R 4 and R 5 each independently are hydrogen, Ar 1 , C 1

-

6 alkyl, C 1

-

6 alkyloxyCl_ 6 alkyl, C1- 6 alkyloxy, C 1

-

6 alkylthio, amino, hydroxycarbonyl,C- 6 alkyloxycarbonyl,.. Cl- 6 alkylS(O)CI- 6 alkyl or C 1

-

6 alkylS(O) 2

C

1

-

6 alkyl;

R

6 and R 7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Ar 2 oxy; 11 WO 2006/135636 PCT/US2006/022142

R

8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, Cl-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, hydroxycarbonylC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, haloC1-6alkyl, CI-6alkyloxyC1-6alkyl, 5 aminocarbonylC 1-6alkyl, Ar 1 , Ar 2 C 1-6alkyloxyC 1-6alkyl, Cl-6alkylthioC1-6alkyl;

R

10 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;

R

1 1 is hydrogen or C1-6alkyl; Ar 1 is phenyl or phenyl substituted with C1-6alkyl,hydroxy,amino, C1-6alkyloxy or 10 halo; Ar 2 is phenyl or phenyl substituted with C1-6alkyl,hydroxy,amino,C1-6alkyloxy or halo. WO-98/40383 and U.S. Patent No. 6,187,786, which are incorporated herein in their 15 entirety, disclose the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (VII)

R

2

R

4 R6 5 (VII) X N A the pharmaceutically acceptable acid addition salts and the stereochemically isomeric 20 forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; -A- is a bivalent radical of formula -CH=CH- (a-1), -CH2-S- (a-6), 25 -CH2-CH2- (a-2), -CH2-CH2-S- (a-7), -CH2-CH2-CH2- (a-3), -CH=N- (a-8), 12 WO 2006/135636 PCT/US2006/022142 -CH2-O- (a-4), -N=N- (a-9), or -CH2-CH2-O- (a-5), -CO-NH- (a-10); wherein optionally one hydrogen atom may be replaced by C 1-4alkyl or Arl;

R

1 and R 2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, 5 trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyCl 6alkyloxy, C 1-6alkyloxyC 1-6alkyloxy, C 1-6alkyloxycarbonyl, aminoCl-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar 2 , Ar 2 -C1-6alkyl, Ar 2 -oxy, Ar 2 -C1-6alkyloxy; or when on adjacent positions R 1 and R 2 taken together may form a bivalent radical of formula 10 -O-CH2-O- (b-1), -O-CH2-CH2-O- (b-2), -O-CH=CH- (b-3), -O-CH2-CH2- (b-4), -O-CH2-CH2-CH2- (b-5), or 15 -CH=CH-CH=CH- (b-6);

R

3 and R 4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar 3 -oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R 3 and R 4 taken together may form a bivalent radical of formula 20 -O-CH2-O- (c-1), -O-CH2-CH2-O- (c-2), or -CH=CH-CH=CH- (c-3);

R

5 is a radical of formula PN N 13 -N (d-1), N --- R (d-2),

R

13 R 25 wherein R 13 is hydrogen, halo, Ar 4 , C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, 13 WO 2006/135636 PCT/US2006/022142 Cl-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C 1-6alkylS(O)2C 1-6alkyl;

R

14 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;

R

6 is hydrogen, hydroxy, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1. 5 6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyCl1-6alkyl, C 1-6alkylthioC 1-6alkyl, aminocarbonylC 1-6alkyl, C 1-6alkyloxycarbonylC 1-6alkyl, CI1-6alkylcarbonyl-C 1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar 5 , Ar 5 -C1-6alkyloxyC1-6alkyl; or a radical of formula 10 -O-R 7 (e-1),

-S-R

7 (e-2),

-N-R

8

R

9 (e-3), wherein R 7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar 6 , Ar 6 -C1.6alkyl, C1-6alkyloxycarbonylC 1-6alkyl, or a radical of formula -Alk 15 OR 10 or -Alk-NR 1 1

R

12 ;

R

8 is hydrogen, C1-6alkyl, Ar 7 or Ar 7 -C1-6alkyl;

R

9 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C 1-6alkylaminocarbonyl, Ar 8 , Ar 8 -C 1-6alkyl, C 1-6alkylcarbonyl C1-6alkyl, Ar 8 -carbonyl, Ar 8 -C1-6alkylcarbonyl, 20 aminocarbonylcarbonyl, CI1-6alkyloxyC 1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C 1-6alkylcarbonylamino, or a radical of formula -Alk-OR 10 or -Alk-NR 1 1

R

12 ; 25 wherein Alk is Cl-6alkanediyl;

R

10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyCl-6alkyl, Ar 9 or Ar 9 -Cl-6alkyl; 14 WO 2006/135636 PCT/US2006/022142

R

1 1 is hydrogen, C1-6alkyl, Cl-6alkylcarbonyl, Ar 10 or Arl 0 -C1-6alkyl;

R

12 is hydrogen, C1-6alkyl, Ar 11 or Ar 1 1

-C

1- 6alkyl; and Ar 1 to Ar 11 are each independently selected from phenyl; or phenyl substituted 5 with halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl. WO-98/49157 and U.S. Patent No. 6,117,432, which are incorporated herein in their entirety, concern the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (VIII)

R

R4 7 R 5 R RW'N. " (VIII) X4 10 R R the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; 15 R 1 and R 2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1 6alkyloxy, CI-6alkyloxyCl-6alkyloxy, C1-6alkyloxycarbonyl, aminoC 1-6alkyloxy, mono- or di(C 1-6alkyl)aminoC 1-6alkyloxy, Ar 1 , ArlC1-6alkyl, Arloxy or ArlC1-6alkyloxy; 20 R 3 and R 4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar 1 oxy, C1-6alkylthio, di(C16alkyI)amino,_trihalomethyl-or-trihalomethoxy;

R

5 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC 1-6alkyl, aminoC 1-6alkyl, C 1-6alkyloxyC 1-6alkyl, Cl-6alkylthioC1-6alkyl, aminocarbonylCl-6alkyl, 25 Ci -6alkyloxycarbonylC 1-6alkyl, C1-6alkylcarbonyl-C 1-6alkyl, 15 WO 2006/135636 PCT/US2006/022142 C1-6alkyloxycarbonyl, mono- or di(C 1-6alkyl)aminoC 1-6alkyl, Ar 1 , ArlC1-6alkyloxyC1-6alkyl; or a radical of formula -O-R10 (a-i), -S-R10 (a-2), 5 -N-R 1 1

R

12 (a-3), wherein R 10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar 1 , ArlC1-6alkyl, C 1-6alkyloxycarbonylC 1-6alkyl, or a radical of formula -Alk

OR

13 or -Alk-NR 14

R

15 ;

R

1 1 is hydrogen, C1-6alkyl, Ar 1 or ArlC1-6alkyl; 10 R 12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C 1-6alkylaminocarbonyl, Ar 1 , Ar 1 C 1-6alkyl, C 1-6alkylcarbonyl C1-6alkyl, Ar 1 carbonyl, ArlC1-6alkylcarbonyl, aminocarbonylcarbonyl, C 1-6alkyloxyC 1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, 15 di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamnino, C1 -6alkylcarbonylamino, or a radical of formula -Alk-OR 13 or -Alk-NR 14

R

15 ; wherein Alk is C1-6alkanediyl;

R

13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, 20 hydroxyC1-6alkyl, Ar 1 or ArlC1-6alkyl;

R

14 is hydrogen, C1-6alkyl, Ar 1 or ArlC1-6alkyl;

R

15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar 1 or ArlC1-6alkyl;

R

6 is a radical of formula AN N6 -N(b-I), R16 (b-2),

R

16 17 25 R 16 WO 2006/135636 PCT/US2006/022142 wherein R 16 is hydrogen, halo, Arl 1 , C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, Ci1-6alkylthioC 1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl; 5 R 17 is hydrogen, C1.6alkyl or di(C1-4alkyl)aminosulfonyl;

R

7 is hydrogen or C1-6alkyl provided that the dotted line does not represent a bond;

R

8 is hydrogen, C1-6alkyl or Ar 2 CH2 or HetlCH2;

R

9 is hydrogen, C1-6alkyl , C1-6alkyloxy or halo; or

R

8 and R 9 taken together to form a bivalent radical of formula 10 -CH=CH- (c-1), -CH2-CH2- (c-2), -CH2-CH2-CH2- (c-3), -CH2-O- (c-4), or -CH2-CH2-O- (c-5); 15 Ar 1 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C 1-6alkyl, C 1-6alkyloxy or trifluoromethyl; Ar 2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl; and Het 1 is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently 20 selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl. WO-00/39082 and U.S. Patent No. 6,458,800, which are incorporated herein in their entirety, describe the preparation, formulation and pharmaceutical properties of farnesyltransferase inhibiting compounds of formula (IX) 25 17 WO 2006/135636 PCT/US2006/022142 (R')r (R2)s

R

3 XYX Y 2 N (IX) x N (R) or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein

=X'-X

2

-X

3 - is a trivalent radical of formula 5 =N-CR 6

=CR

7 - (x-1), =CR6-CR 7

=CR

8 - (x-6),

=N-N=CR

6 - (x-2), =CR 6

-N=CR

7 - (x-7), =N-NH-C(=O)- (x-3), =CR 6 -NH-C(=O)- (x-8), or =N-N=N- (x-4), =CR 6 -N=N- (x-9); =N-CR6=N- (x-5), 67 10 wherein each R 6 , R and R 8 are independently hydrogen, Cl- 4 alkyl, hydroxy,

CI-

4 alkyloxy, aryloxy, CI 4 alkyloxycarbonyl, hydroxyC 1 -4alkyl,

CI-

4 alkyloxyC 1

-

4 alkyl, mono- or di(C1- 4 alkyl)aminoC 1

-

4 alkyl, cyano, amino, thio, Cl- 4 alkylthio, arylthio or aryl; >yly2 is a trivalent radical of formula 15 >CH-CHR 9 - (y-l), >C=N- (y-2),

>CH-NR

9 - (y-3),or

>C=CR

9 - (y-4); wherein each R 9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, 20 hydroxyC- 4 alkyl, cyano, carboxyl, C 1

-

4 alkyl, C1- 4 alkyloxy, CI- 4 alkyloxyCl_ 4 alkyl, C 1

-

4 alkyloxycarbonyl, mono- or di(C- 4 alkyl)amino, mono- or di(C 1

-

4 alkyl)aminoC1- 4 alkyl, aryl; r and s are each independently 0, 1, 2, 3, 4 or 5; tis-0l;1 2-or-3; 25 each R 1 and R 2 are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C 2

-

6 alkenyl, C 1

-

6 alkyloxy, hydroxyC1- 6 alkyloxy, Cz_ 6 alkylthio,

C

1 i- 6 alkyloxyCI- 6 alkyloxy, C-6alkyloxycarbonyl, aminoC 1

-

6 alkyloxy, mono- or 18 WO 2006/135636 PCT/US2006/022142 di(CI.6alkyl)amino, mono- or di(CI.

6 alkyl)aminoC.

6 alkyloxy, aryl, arylCI-6alkyl, aryloxy or arylC 1

.

6 alkyloxy, hydroxycarbonyl, C1.6alkyloxycarbonyl, aminocarbonyl, aminoC 1

.

6 alkyl, mono- or di(Cl.6alkyl)aminocarbonyl, mono- or di(C1-6alkyl)aminoCI.

6 alkyl; or 5 two R 1 or R 2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula

-O-CH

2 -O- (a-i),

-O-CH

2

-CH

2 -O- (a-2), -O=CH=CH- (a-3), 10 -O-CH 2

-CH

2 - (a-4),

-O-CH

2

-CH

2 - CH 2 - (a-5), or -CH=CH-CH=CH- (a-6);

R

3 is hydrogen, halo, C1- 6 alkyl, cyano, haloC 1

I

6 alkyl, hydroxyC 1

-

6 alkyl, cyanoCI 6 alkyl, aminoC 1

-

6 alkyl, Cl 6 alkyloxyCl.

6 alkyl, C1- 6 alkylthioC1- 6 alkyl, 15 aminocarbonylC 1

-

6 alkyl, hydroxycarbonyl, hydroxycarbonylC 1

I

6 alkyl,

C

6 alkyloxycarbonylC 1

-

6 alkyl, C1- 6 alkylcarbonylC 1

-

6 alkyl, Cl 6 alkyloxycarbonyl, aryl, arylC 1 _6alkyloxyC1-6alkyl, mono- or di(CI- 6 alkyl)aminoC 1

-

6 alkyl; or a radical of formula -O-R (b-i), 20 -S-Rio (b-2), -NRlR12 (b-3), wherein R 1 0 is hydrogen, C1- 6 alkyl, C1- 6 alkylcarbonyl, aryl, arylCl- 6 alkyl, Cl- 6 alkyloxycarbonylC 1 -6alkyl, or a radical of formula -Alk-OR 13 or -Alk-NR 14

R

1 5 ; 25 R i is hydrogen, Ci 6 alkyl, aryl or arylCz_ 6 alkyl;

R

1 2 is hydrogen, CI.

6 alkyl, aryl, hydroxy, amino, Cp6alkyloxy,

C

1

-

6 alkylcarbonylC- 6 alkyl, arylC 1

-

6 alkyl, C1- 6 alkylcarbonylamino, mono- or di(C- 6 alkyl)amino, Ci -6alkylcarbonLyl,_aminocarbonyl, arylcarbonyl, haloCI 6 alkylcarbonyl, arylC 1

-

6 alkylcarbonyl, 30 C 1

-

6 alkyloxycarbonyl, Cl-6alkyloxyCl6alkylcarbonyl, mono- or di(CI-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more 19 WO 2006/135636 PCT/US2006/022142 substituents independently selected from aryl or C1i.- 3 alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(CI-6alkyl)aminoCl.

6 alkylcarbonyl, or a radical of formula -Alk-OR 3 or -Alk-NRI 4 R"; 5 wherein Alk is C 1

.

6 alkanediyl;

R

1 3 is hydrogen, C1- 6 alkyl, CI-6alkylcarbonyl, hydroxyC 1

-

6 alkyl, aryl or arylC 1

.

6 alkyl;

R

14 is hydrogen, C1- 6 alkyl, aryl or arylC 1

-

6 alkyl;

R

1 5 is hydrogen, C1 6 alkyl, C 1

.

6 alkylcarbonyl, aryl or arylC 1

-

6 alkyl; 10 R 4 is a radical of formula N 16 -N (c-),

R

16 (c-2),

R

16 R17 R wherein R 16 is hydrogen, halo, aryl, C 1

-

6 alkyl, hydroxyCi-.

6 alkyl,

CI-

6 alkyloxyC.

6 alkyl, C1- 6 alkyloxy, C1-6alkylthio, amino, mono- or di(C 1 -4alkyl)amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, 15 C1-6alkylthioC1- 6 alkyl, C1- 6 alkylS(O)Ci- 6 alkyl or CI- 6 alkylS(O) 2

C

1

-

6 alkyl;

R

16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning ofR 16 when bound to the nitrogen is limited to hydrogen, aryl, C1- 6 alkyl, hydroxyC 1

-

6 alkyl, C1-6alkyloxyClI 6 alkyl, Cl-6alkyloxycarbonyl, C1- 6 alkylS(O)C 1

-

6 alkyl or 20 CI-6alkylS(O) 2 C1- 6 alkyl;

R"

7 is hydrogen, C1- 6 alkyl, C1.6alkyloxyC1- 6 alkyl, arylC1- 6 alkyl, trifluoromethyl or di(Cl- 4 alkyl)aminosulfonyl;

R

5 is CI 6 alkyl , C1- 6 alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each 25 independently selected from halo, C 1

-

6 alkyl, Ci_ 6 alkyloxy or trifluoromethyl. In-addition-to-the-farnesyltrainsferase in-iiitor-o-f formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) above, other farnesyltransferase inhibitors known in the art include: Arglabin (i.e. 1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olide 30 described in WO-98/28303 (NuOncology Labs); perrilyl alcohol described in WO 99/45912 (Wisconsin Genetics); SCH-66336, i.e. (+)-(R)-4-[2-[4-(3,10-dibromo-8 20 WO 2006/135636 PCT/US2006/022142 chloro-5,6-dihydro- 11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)piperidin- 1 -yl]-2 oxoethyl]piperidine-1-carboxamrnide, described in U.S. Patent No. 5874442 (Schering); L778123, i.e. 1-(3-chlorophenyl)-4-[ 1-( 4 -cyanobenzyl)-5-imidazolylmethyl]-2 piperazinone, described in WO-00/01691 (Merck); compound 2(S)-[2(S)-[2(R) 5 amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl methionine sulfone described in WO-94/10138 (Merck); and BMS 214662, i.e. (R) 2,3,4,5-tetrahydro-l1-(IH-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2 thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile, described in WO 97/30992 (Bristol Myers Squibb); and Pfizer compounds (A) and (B) described in WO 10 00/12498 and WO-00/12499: C1 Cl NH2

NH

2 S N H3C N H 3 C

CH

3 CH 3 (A) (B) FLT3 kinase inhibitors known in the art include: AG1295 and AG1296; Lestaurtinib (also known as CEP 701, formerly KT-5555, Kyowa Hakko, licensed to Cephalon); 15 CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (Chiron Corp.); EB-10 and IMC EBO10 (ImClone Systems Inc.); GTP 14564 (Merk Biosciences UK). Midostaurin (also known as PKC 412 Novartis AG); MLN 608 (Millennium USA); MLN-518 (formerly CT53518, COR Therapeutics Inc., licensed to Millennium Pharmaceuticals Inc.); MLN-608 (Millennium Pharmaceuticals Inc.); SU-11248 (Pfizer USA); SU 20 11657 (Pfizer USA); SU-5416 and SU 5614; THRX-165724 (Theravance Inc.); AMI 10706 (Theravance Inc.); VX-528 and VX-680 (Vertex Pharmaceuticals USA, licensed to Novartis (Switzerland), Merck & Co USA); and XL 999 (Exelixis USA). See also Levis, M., K. F. Tse, et al. (2001) "A FLT3 tyrosine kinase inhibitor is 25 selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations." Blood 98(3): 885-7; Tse KF, et al. (2001) Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia. 21 WO 2006/135636 PCT/US2006/022142 Jul; 15(7):1001-10; Smith, B. Douglas et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 2004; 103: 3669 - 3676; Griswold, Ian J. et al. Effects of MLN518, A Dual FLT3 and KIT Inhibitor, on Normal and Malignant 5 Hematopoiesis. Blood, Jul 2004; [Epub ahead of print]; Yee, Kevin W. H. et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood, Sep 2002; 100: 2941 - 294; O'Farrell, Anne-Marie et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, May 2003; 101: 3597 - 3605; Stone, R.M. et al. PKC 412 FLT3 10 inhibitor therapy in AML: results of a phase II trial. Ann Hematol. 2004; 83 Suppl 1:S89-90; and Murata, K. et al. Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem. 2003 Aug 29; 278(35):32892-8; Levis, Mark et al. Novel FLT3 tyrosine kinase inhibitors. Expert Opin. Investing. 15 Drugs (2003) 12(12) 1951-1962; Levis, Mark et al. Small Molecule FLT3 Tyrosine Kinase Inhibitors. Current Pharmaceutical Design, 2004, 10, 1183-1193. SUMMARY OF THE INVENTION 20 The present invention comprises a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a FLT3 kinase inhibitor and a farnesyl transferase inhibitor. Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell 25 proliferative disorder or a disorder related to FLT3, the methods comprising generally administering to the subject a prophylactically effective amount of a FLT3 kinase inhibitor and a farnesyl transferase inhibitor. The FLT3 kinase inhibitor and farnesyl transferase inhibitor can be administered as a unitary pharmaceutical composition comprising a FLT3 kinase inhibitor, a farnesyl transferase-inhibitor-and-a 30 pharmaceutically acceptable carrier, or as separate pharmaceutical compositions: (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier. 22 WO 2006/135636 PCT/US2006/022142 The invention further encompasses a multiple component therapy for treating or inhibiting onset of a cell proliferative disorder or a disorder related to FLT3 in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and one 5 or more other anti-cell proliferation therapy(ies) including chemotherapy, radiation therapy, gene therapy and immunotherapy. Other embodiments, features, advantages, and aspects of the invention will become apparent from the detailed description hereafter in reference to the drawing figures. 10 DESCRIPTION OF THE DRAWINGS Figure 1. Effects of oral administration of compounds of the present invention on the 15 growth of MV4-11 tumor xenografts in nude mice. Figure 2. Effects of oral administration of compounds of the present invention on the final weight of MV4-1 tumor xenografts in nude mice. 20 Figure 3. FLT3 phosphorylation in MV4-11 tumors obtained from mice treated with compounds of the present invention. Figure 4. Figure 4 is intentionally omitted. 25 Figure 5. Compounds tested for inhibition of FLT3-dependent proliferation. Figure 6.1-6.8. Dose responses of single agents on FLT3 dependent AML cell proliferation. 30 Figure 7a-c. A low dose of a FLT3 inhibitor significantly shifts the potency of Tipifarnib in FLT3 dependent cells. 23 WO 2006/135636 PCT/US2006/022142 Figure 8a-d. Single dose combinations of a FLT3 inhibitor Compound (A) and Tipifarnib or Cytarabine synergistically inhibit FLT3-dependent cell line growth. Figure 9a-b. Single dose combination of FLT3 inhibitor Compounds B and D with 5 either Tipifarnib or Cytarabine synergistically inhibits MV4-11 cell growth. Figure 10.1. FLT3 inhibitor Compound A and Tipifarnib synergistically inhibit the proliferation of FLT3 dependent cells as measured by the method of Chou ad Talalay. 10 Figure 10.2. FLT3 inhibitor Compound B and Tipifarnib synergistically inhibit the proliferation of FLT3 dependent cells as measured by the method of Chou ad Talalay. Figure 10.3. FLT3 inhibitor Compound C and Tipifarnib synergistically inhibit the proliferation of FLT3 dependent cells as measured by the method of Chou ad Talalay. 15 Figure 10.4. FLT3 inhibitor Compound D and Tipifarnib synergistically inhibit the proliferation of FLT3 dependent cells as measured by the method of Chou ad Talalay. Figure 10.5. FLT3 inhibitor Compound H and Tipifarnib synergistically inhibit the 20 proliferation of MV4-11 cells as measured by the method of Chou and Talalay. Figure 10.6. FLT3 inhibitor Compound E and Zarnestra synergistically inhibit the proliferation of MV4-11 cells as measured by the method of Chou and Talalay. 25 Figure 10.7. FLT3 inhibitor Compound F and Tipifarnib synergistically inhibit the proliferation of FLT3 dependent MV4-11 cells as measured by the method of Chou ad Talalay. Figure 10.8.-FLT-3 inhibitor-C-ompound-G-and-Tipifarnib synergisticallyhiibift-thNe 30 proliferation of FLT3 dependent MV4-11 cells as measured by the method of Chou ad Talalay. 24 WO 2006/135636 PCT/US2006/022142 Figure 11a-c. The combination of a FLT3 inhibitor and an FTI synergistically induces apoptosis of MV4-11 cells. Figure 12 a-d. Dose responses of single agent induction of caspase 3/7 activation and 5 apoptosis of FLT3 dependent MV4-11 cells. Figure 13.1. FLT3 inhibitor Compound B and Tipifarnib synergistically induce the activation of caspase 3/7 in FLT3 dependent MV4-11 cells as measured by the method of Chou ad Talalay. 10 Figure 13.2. FLT3 inhibitor Compound C and Tipifarnib synergistically induce the activation of caspase 3/7 in FLT3 dependent MV4-11 cells as measured by the method of Chou ad Talalay. 15 Figure 13.3. FLT3 inhibitor Compound D and Tipifarnib synergistically induce the activation of caspase 3/7 in FLT3 dependent MV4-11 cells as measured by the method of Chou ad Talalay. Figure 14. Tipifarnib increases the potency of FLT3 inhibitor Compound A 20 inhibition of FLT3 and MapKinase phosphorylation in MV4-11 cells. Figure 15. Effects over time on tumor volume of orally administered FLT3 inhibitor CompoundB and Tipifarnib, alone and in combination, on the growth of MV-4-11 tumor xenografts in nude mice. 25 Figure 16. Effects on tumor volume of orally administered FLT3 inhibitor Compound B and Tipifarnib alone or in combination on the growth of MV-4-11 tumor xenografts in nude mice at the terminal study day. 30 Figure 17. Effects on tumor weight of orally administered FLT3 inhibitor Compound B and Tipifarnib alone or in combination on the growth of MV-4-11 tumor xenografts in nude mice at the terminal study day. 25 WO 2006/135636 PCT/US2006/022142 Figure 18.Effects of oral administration of FLT3 inhibitor Compound D of the present invention on the growth of MV4-11 tumor xenografts in nude mice. Figure 19. Effects of oral administration of FLT3 inhibitor Compound D of the 5 present invention on the final weight of MV4-11 tumor xenografts in nude mice. Figure 20. Effects of oral administration of FLT3 inhibitor Compound D of the present invention on mouse body weight. 10 Figure 21. FLT3 phosphorylation in MV4-11 tumors obtained from mice treated with FLT3 inhibitor Compound D of the present invention. Figure 22. Effects over time on tumor volume of orally administered FLT3 inhibitor Compound D and Tipifarnib, alone and in combination, on the growth of MV-4-11 15 tumor xenografts in nude mice. Figure 23.Effects on tumor volume of orally administered FLT3 inhibitor Compound D and Tipifarnib alone or in combination on the growth of MV-4-11 tumor xenografts in nude mice. 20 Figure 24. Effects of orally administered FLT3 inhibitor Compound D and Tipifarnib alone or in combination on the final weight of MV-4-11 tumor xenografts in nude mice. 25 DETAIL DESCRIWON OF THE INVENTION ANDPREFERREDEMBODIMENTS The terms "comprising", "including", and "containing" are used herein in their open, non-limited sense. 30 The present invention comprises a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a FLT3 kinase inhibitor and a farnesyl transferase inhibitor. 26 WO 2006/135636 PCT/US2006/022142 An embodiment of the present invention comprises a method for reducing or inhibiting FLT3 tyrosine kinase activity in a subject comprising the administration of a FLT3 kinase inhibitor and a farnesyl transferase inhibitor to the subject. 5 An embodiment of the present invention comprises a method of treating disorders related to FLT3 tyrosine kinase activity or expression in a subject comprising the administration of a FLT3 kinase inhibitor and a farnesyl transferase inhibitor to the subject. 10 An embodiment of the present invention comprises a method for reducing or inhibiting the activity of FLT3 tyrosine kinase in a cell comprising the step of contacting the cell with a FLT3 kinase inhibitor and a farnesyl transferase inhibitor. 15 The present invention also provides a method for reducing or inhibiting the expression of FLT3 tyrosine kinase in a subject comprising the step of administering a FLT3 kinase inhibitor and a farnesyl transferase inhibitor to the subject. The present invention further provides a method of inhibiting cell proliferation in a 20 cell comprising the step of contacting the cell with a FLT3 kinase inhibitor and a farnesyl transferase inhibitor. The kinase activity of FLT3 in a cell or a subject can be determined by procedures well known in the art, such as the FLT3 kinase assay described herein. 25 The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. rhe-term"contacting" as-used-herein,-refers-to-the-addition-ofCffoiipoidto- cells such 30 that compound is taken up by the cell. 27 WO 2006/135636 PCT/US2006/022142 In other embodiments to this aspect, the present invention provides both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3. 5 In one example, the invention provides methods for preventing in a subject a cell proliferative disorder or a disorder related to FLT3, comprising administering to the subject a prophylactically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a 10 pharmaceutically acceptable carrier. In one example, the invention provides methods for preventing in a subject a cell proliferative disorder or a disorder related to FLT3, comprising administering to the subject a prophylactically effective amount of a pharmaceutical composition 15 comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier. Administration of said prophylactic agent(s) can occur prior to the manifestation of symptoms characteristic of the cell proliferative disorder or disorder related to FLT3, 20 such that a disease or disorder is prevented or, alternatively, delayed in its progression. In another example, the invention pertains to methods of treating in a subject a cell proliferative disorder or a disorder related to FLT3 comprising administering to the 25 subject a therapeutically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier. 30 In another example, the invention pertains to methods of treating in a subject a cell proliferative disorder or a disorder related to FLT3 comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition 28 WO 2006/135636 PCT/US2006/022142 comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier. Administration of said therapeutic agent(s) can occur concurrently with the 5 manifestation of symptoms characteristic of the disorder, such that said therapeutic agent serves as a therapy to compensate for the cell proliferative disorder or disorders related to FLT3. The FLT3 kinase inhibitor and farnesyl transferase inhibitor can be administered as a 10 unitary pharmaceutical composition comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, or as separate pharmaceutical compositions: (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a 15 pharmaceutically acceptable carrier. In the latter case, the two pharmaceutical compositions may be administered simultaneously (albeit in separate compositions), sequentially in either order, at approximately the same time, or on separate dosing schedules. On separate dosing schedules, the two compositions are administered within a period and in an amount and manner that is sufficient to ensure that an 20 advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the agent being administered, their route of administration, the particular 25 tumor being treated and the particular host being treated. As will be understood by those of ordinary skill in the art, the optimum method and order of administration and the dosage amounts and regime of the FLT3 kinase inhibitor-and-farnesyl transferaseinhibitor-can-be-rea-dily-dt-fiiil-ed b -flios-e-skliled 30 in the art using conventional methods and in view of the information set out herein. Generally, the dosage amounts and regime of the FLT3 kinase inhibitor and farnesyl transferase inhibitor will be similar to or less than those already employed in clinical 29 WO 2006/135636 PCT/US2006/022142 therapies where these agents are administered alone, or in combination with other chemotherapeutics. The term "prophylactically effective amount" refers to an amount of an active 5 compound or pharmaceutical agent that inhibits or delays in a subject the onset of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician. The term "therapeutically effective amount" as used herein, refers to an amount of 10 active compound or pharmaceutical agent that elicits the biological or medicinal response in a subject that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. 15 Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition(s). As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product 20 which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. As used herein, the terms "disorders related to FLT3", or "disorders related to FLT3 receptor", or "disorders related to FLT3 receptor tyrosine kinase" shall include 25 diseases associated with or implicating FLT3 activity, for example, the overactivity of FLT3, and conditions that accompany with these diseases. The term "overactivity of FLT3 "refers to either 1) FLT3 expression in cells which normally do not express FLT3; 2) FLT3 expression by cells which normally do not express FLT3; 3) increased ELT3-expression-leading-to-unwanted-cell- proliferationor4)-mutati-filadT-nhg to 30 constitutive activation of FLT3. Examples of "disorders related to FLT3" include disorders resulting from over stimulation of FLT3 due to abnormally high amount of FLT3 or mutations in FLT3, or disorders resulting from abnormally high amount of FLT3 activity due to abnormally high amount of FLT3 or mutations in FLT3. It is 30 WO 2006/135636 PCT/US2006/022142 known that overactivity of FLT3 has been implicated in the pathogenesis of a number of diseases, including the cell proliferative disorders, neoplastic disorders and cancers listed below. 5 The term "cell proliferative disorders" refers to unwanted cell proliferation of one or more subset of cells in a multicellular organism resulting in harm (i.e., discomfort or decreased life expectancy) to the multicellular organisms. Cell proliferative disorders can occur in different types of animals and humans. For example, as used herein "cell proliferative disorders" include neoplastic disorders and other cell proliferative 10 disorders. As used herein, a "neoplastic disorder" refers to a tumor resulting from abnormal or uncontrolled cellular growth. Examples of neoplastic disorders include, but are not limited to, hematopoietic disorders such as, for instance, the myeloproliferative 15 disorders, such as thrombocythemia, essential thrombocytosis (ET), angiogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (IMF), polycythemia vera (PV), the cytopenias, and pre-malignant myelodysplastic syndromes; cancers such as glioma cancers, lung cancers, breast cancers, colorectal cancers, prostate cancers, gastric 20 cancers, esophageal cancers, colon cancers, pancreatic cancers, ovarian cancers, and hematoglogical malignancies, including myelodysplasia, multiple myeloma, leukemias and lymphomas. Examples of hematological malignancies include, for instance, leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma -- for instance, acute lymphocytic 25 leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic-leukemia-(JMML),-adult-T-cell-AL,-AML with-trilinege 30 myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma, (MM). 31 WO 2006/135636 PCT/US2006/022142 In a further embodiment to this aspect, the invention encompasses a multiple component therapy for treating or inhibiting onset of a cell proliferative disorder or a disorder related to FLT3 in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a FLT3 kinase inhibitor, a 5 farnesyl transferase inhibitor and and one or more other anti-cell proliferation therapy(ies) including chemotherapy, radiation therapy, gene therapy and immunotherapy. As used herein, "chemotherapy" refers to a therapy involving a chemotherapeutic 10 agent. A variety of chemotherapeutic agents may be used in the multiple component treatment methods disclosed herein. Chemotherapeutic agents contemplated as exemplary, include, but are not limited to: platinum compounds (e.g.,cisplatin, carboplatin, oxaliplatin); taxane compounds (e.g., paclitaxcel, docetaxol); campotothecin compounds (irinotecan, topotecan); ; vinca alkaloids (e.g., vincristine, 15 vinblastine, vinorelbine); anti-tumor nucleoside derivatives (e.g., 5-fluorouracil, leucovorin, gemcitabine, capecitabine) ; alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, thiotepa); epipodophyllotoxins / podophyllotoxins (e.g. etoposide, teniposide); aromatase inhibitors (e.g., anastrozole, letrozole, exemestane); anti-estrogen compounds (e.g., tamoxifen, fulvestrant), antifolates (e.g., premetrexed 20 disodium); hypomethylating agents (e.g., azacitidine); biologics (e.g., gemtuzamab, cetuximab, rituximab, pertuzumab, trastuzumab, bevacizumab, erlotinib); antibiotics/anthracyclines (e.g. idarubicin, actinomycin D, bleomycin, daunorubicin, doxorubicin, mitomycin C, dactinomycin, carminomycin, daunomycin); antimetabolites (e.g., aminopterin, clofarabine, cytosine arabinoside, methotrexate); 25 tubulin-binding agents (e.g. combretastatin, colchicine, nocodazole); topoisomerase inhibitors (e.g., camptothecin). Further useful agents include verapamil, a calcium antagonist found to be useful in combination with antineoplastic agents to establish chemosensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiatethe efficacy-of-such-compounds-in-drug-sensitive malignanciesc.Se 30 Simpson WG, The calcium channel blocker verapamil and cancer chemotherapy. Cell Calcium. 1985 Dec;6(6):449-67. Additionally, yet to emerge chemotherapeutic agents are contemplated as being useful in combination with the compound of the present invention. 32 WO 2006/135636 PCT/US2006/022142 In another embodiment of the present invention, the FLT3 kinase inhibitor and farnesyl transferase inhibitor may be administered in combination with radiation therapy. As used herein, "radiation therapy" refers to a therapy that comprises 5 exposing the subject in need thereof to radiation. Such therapy is known to those skilled in the art. The appropriate scheme of radiation therapy will be similar to those already employed in clinical therapies wherein the radiation therapy is used alone or in combination with other chemotherapeutics. 10 In another embodiment of the present invention, the FLT3 kinase inhibitor and farnesyl transferase inhibitor may be administered in combination with gene therapy. As used herein, "gene therapy" refers to a therapy targeting on particular genes involved in tumor development. Possible gene therapy strategies include the restoration of defective cancer-inhibitory genes, cell transduction or transfection with 15 antisense DNA corresponding to genes coding for growth factors and their receptors, RNA-based strategies such as ribozymes, RNA decoys, antisense messenger RNAs and small interfering RNA (siRNA) molecules and the so-called 'suicide genes'. In other embodiments of this invention, the FLT3 kinase inhibitor and farnesyl 20 transferase inhibitor may be administered in combination with immunotherapy. As used herein, "immunotherapy" refers to a therapy targeting particular protein involved in tumor development via antibodies specific to such protein. For example, monoclonal antibodies against vascular endothelial growth factor have been used in treating cancers. 25 Where one or more additional chemotherapeutic agent(s) are used in conjunction with the FLT3 kinase inhibitor and farnesyl transferase inhibitor, the additional chemotherapeutic agent(s), the FLT3 kinase inhibitor and the farnesyl transferase inhibitor maybeadministered-simultaneously-(e.g-in-separate-or-utritay. 30 compositions) sequentially in any order, at approximately the same time, or on separate dosing schedules. In the latter case, the pharmaceuticals will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous and synergistic effect is achieved. It will be appreciated that the 33 WO 2006/135636 PCT/US2006/022142 preferred method and order of administration and the respective dosage amounts and regimes for the additional chemotherapeutic agent(s) will depend on the particular chemotherapeutic agent(s) being administered in conjunction with the FLT3 kinase inhibitor and farnesyl transferase inhibitor, their route of administration, the particular 5 tumor being treated and the particular host being treated. As will be understood by those of ordinary skill in the art, the appropriate doses of the additional chemotherapeutic agent(s) will be generally similar to or less than those already employed in clinical therapies wherein the chemotherapeutics are administered alone or in combination with other chemotherapeutics. 10 The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein. 15 By way of example only, platinum compounds are advantageously administered in a dosage of 1 to 500 mg per square meter (mg/m 2 ) of body surface area, for example 50 to 400 mg/m 2 , particularly for cisplatin in a dosage of about 75 mg/m 2 and for carboplatin in about 300mg/m 2 per course of treatment. Cisplatin is not absorbed orally and must therefore be delivered via injection intravenously, subcutaneously, 20 intratumorally or intraperitoneally. By way of example only, taxane compounds are advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 75 to 250 mg/m 2 , particularly for paclitaxel in a dosage of about 175 to 250 mg/m 2 25 and for docetaxel in about 75 to 150 mg/m 2 per course of treatment. By way of example only, camptothecin compounds are advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m 2 ) of body surface area, for example-Lto-300 mg/m particularly-for irinotecan-int a-dose-f-ab-ft-l0-t- 35 30 mg/m 2 and for topotecan in about 1 to 2 mg/m 2 per course of treatment. By way of example only, vinca alkaloids may be advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m ) of body surface area, particularly for 34 WO 2006/135636 PCT/US2006/022142 vinblastine in a dosage of about 3 to 12 mg/m , for vincristine in a dosage of about 1 to 2 mg/m 2 , and for vinorelbine in dosage of about 10 to 30 mg/m 2 per course of treatment. 5 By way of example only, anti-tumor nucleoside derivatives may be advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m 2 ) of body surface area, for example 700 to 1500 mg/m 2 . 5-fluorouracil (5-FU) is commonly used via intravenous administration with doses ranging from 200 to 500mg/m 2 (preferably from 3 to 15 mg/kg/day). Gemcitabine is advantageously administered in a dosage of 10 about 800 to 1200 mg/m 2 and capecitabine is advantageously administered in about 1000 to 2500 mg/m 2 per course of treatment. By way of example only, alkylating agents may be advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m 2 ) of body surface area, for example 15 120 to 200 mg/m 2 , particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m 2 , for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg of body weight, for carmustine in a dosage of about 150 to 200 mg/m 2 , and for lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment. 20 By way of example only, podophyllotoxin derivatives may be advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m2) of body surface area, for example 50 to 250 mg/m 2 , particularly for etoposide in a dosage of about 35 to 100 mg/m 2 and for teniposide in about 50 to 250 mg/m 2 per course of treatment. 25 By way of example only, anthracycline derivatives may be advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m 2 ) of body surface area, for example 15 to 60 mg/m 2 , particularly for doxorubicin in a dosage of about 40 to 75 mg/m 2 , for daunorubicin in a dosage of about 25 to 45mg/m 2 , and for idarubicin ina-dosage-of.about-10-to-1-5-mg/mn per-course-of-treatment. 30 By way of example only, anti-estrogen compounds may be advantageously administered in a dosage of about 1 to 100mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a 35 WO 2006/135636 PCT/US2006/022142 dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. 5 Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20 100mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60mg once a day. Exemestane is advantageously administered orally in a dosage of about 25mg once a day. 10 By way of example only, biologics may be advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m 2 ) of body surface area, or as known in the art, if different. For example, trastuzumab is advantageously administered in a dosage of 1 to 5 mg/m 2 particularly 2 to 4mg/nm 2 per course of treatment. 15 Dosages may be administered, for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days. The FLT3 kinase inhibitor and farnesyl transferase inhibitor can be administered to a 20 subject systemically, for example, intravenously, orally, subcutaneously, intramuscular, intradermal, or parenterally. The FLT3 kinase inhibitor and farnesyl transferase inhibitor can also be administered to a subject locally. Non-limiting examples of local delivery systems include the use of intraluminal medical devices that include intravascular drug delivery catheters, wires, pharmacological stents and 25 endoluminal paving. The FLT3 kinase inhibitor and farnesyl transferase inhibitor can further be administered to a subject in combination with a targeting agent to achieve high local concentration of the FLT3 kinase inhibitor and farnesyl transferase inhibitor at the target site. In addition, the FLT3 kinase inhibitor and farnesyl .transferase-inhibitor-may-be-f4ormulated-for-fast-release-or-slo -release-withthe 30 objective of maintaining the drugs or agents in contact with target tissues for a period ranging from hours to weeks. 36 WO 2006/135636 PCT/US2006/022142 The separate pharmaceutical compositions comprising the FLT3 kinase inhibitor in association with a pharmaceutically acceptable carrier, and the farnesyl transferase inhibitor in association with a pharmaceutically acceptable carrier may contain between about 0.1 mg and 1000 mg, preferably about 100 to 500 mg, of the individual 5 agents compound, and may be constituted into any form suitable for the mode of administration selected. The unitary pharmaceutical composition comprising the FLT3 kinase inhibitor and farnesyl transferase inhibitor in association with a pharmaceutically acceptable carrier 10 may contain between about 0.1 mg and 1000 mg, preferably about 100 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. The phrases "pharmaceutically acceptable" refer to molecular entities and 15 compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. Veterinary uses are equally included within the invention and "pharmaceutically acceptable" formulations include formulations for both clinical and/or veterinary use. 20 Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and 25 liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions. The-pharmaceutical-compositionrfs of-th-rese-nf-in viiiion, whether unitary or 30 separate, may be formulated for slow release of the FLT3 kinase inhibitor and farnesyl transferase inhibitor. Such a composition, unitary or separate, includes a slow release carrier (typically, a polymeric carrier) and one, or in the case of the 37 WO 2006/135636 PCT/US2006/022142 unitary composition, both, of the FLT3 kinase inhibitor and farnesyl transferase inhibitor. Slow release biodegradable carriers are well known in the art. These are materials 5 that may form particles that capture therein an active compound(s) and slowly degrade/dissolve under a suitable environment (e.g., aqueous, acidic, basic, etc) and thereby degrade/dissolve in body fluids and release the active compound(s) therein. The particles are preferably nanoparticles (i.e., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm 10 in diameter). FARNESYLTRANSFERASE INHIBITORS 15 Examples of farnesyltransferase inhibitors which may be employed in the methods or treatments in accordance with the present invention include the farnesyltransferase inhibitors ("FTIs") of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) above. 20 Preferred FTIs include compounds of formula (I), (II) or (III): R3 R16 R4 R3 R16 R4 R2 H R;--5 R ~ H -- R 5 Ri2"-g R17 .t R R9 38 R19 R R7 38 WO 2006/135636 PCT/US2006/022142 R3 16 R R2 HN R5 R179 R R19 R IB R7 (III) the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond; 5 X is oxygen or sulfur;

R

1 is hydrogen, C1-12alkyl, Arl 1 , Ar 2 C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C 1-6alkyl)aminoCl-6alkyl, aminoC1-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(O)2-R 9 , 10 wherein Alk 1 is C1-6alkanediyl,

R

9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C 1-8alkylamino substituted with C 1-6alkyloxycarbonyl;

R

2 , R 3 and R 16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C 1-6alkyloxy, hydroxyC 1-6alkyloxy, C 1-6alkyloxyC 1-6alkyloxy, 15 aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar 1 , Ar 2 C1-6alkyl, Ar 2 oxy, Ar 2 C1-6alkyloxy, hydroxycarbonyl, C 1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4 dimethyloxazolyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical 20 of formula -O-CH2-O- (a-i), -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), 39 WO 2006/135636 PCT/US2006/022142 -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6);

R

4 and R 5 each independently are hydrogen, halo, Ar 1 , C1-6alkyl, hydroxyC1 6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, 5 hydroxycarbonyl, C1-6alkyloxycarbonyl, C 1-6alkylS(O)C 1-6alkyl or C 1 6alkylS(O)2C 1-6alkyl;

R

6 and R 7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar 2 oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or when on adjacent positions R 6 and R 7 taken together may form a bivalent radical 10 of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2);

R

8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylCli-6alkyl, cyanoC1-6alkyl, Cl-6alkyloxycarbonylC1-6alky1, 15 carboxyCl-6alkyl, hydroxyCl-6alkyl, aminoCi-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C 1-6alkyloxyC 1-6alkyl, aminocarbonylC 1-6alkyl, or a radical of formula -O-R10 (b-1), -S-R10 (b-2), 20 -N-R 1 1

R

12 (b-3), wherein R 10 is hydrogen, C1-6alkyl, Cl-6alkylcarbonyl, Ar 1 , Ar 2 C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula -Alk 2 OR 13 or -Alk 2

-NR

14

R

15 ;

R

11 is hydrogen, C1-12alkyl, Ar 1 or Ar 2 C1-6alkyl; 25 R 12 is hydrogen, Cl-6alkyl, Cl-16alkylcarbonyl, C1-6alkyloxycarbonyl, Cl-6alkylaminocarbonyl, Ar 1 , Ar 2 C1-6alkyl, C1-6alkylcarbonylCl-6alkyl, a natural amino acid, Ar 1 carbonyl, Ar 2 C 1-6alkylcarbonyl, aminocarbonylcarbonyl, C 1-6alkyloxyC 1 6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, 40 WO 2006/135636 PCT/US2006/022142 di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical of formula -Alk 2

-OR

13 or -Alk 2

-NR

14

R

15 ; wherein Alk 2 is C1-6alkanediyl; 5 R 13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC 1-6alkyl, Ar 1 or Ar 2 C 1-6alkyl;

R

14 is hydrogen, C1-6alkyl, Ar 1 or Ar 2 C1- 6 alkyl;

R

15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Arl or Ar 2 C 1-6alkyl; 10 R 17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Arl;

R

18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;

R

19 is hydrogen or C1- 6 alkyl; Ar 1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C 1-6alkyloxy or halo; and 15 Ar 2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo. In Formulas (I), (II) and (III), R 4 or R 5 may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by 20 R 4 or R 5 and the meaning of R 4 and R 5 when bound to the nitrogen is limited to hydrogen, Ar 1 , C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1 6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl, C1-6alkylS(O)2C1-6alkyl. Preferably the substituent R 18 in Formulas (I), (II) and (I) is situated on the 5 or 7 25 -position-of the quinolinone-moiety and-substituent-R 1 9-is-sitrated-o-th-& position when R 18 is on the 7-position. Preferred examples of FTIs are those compounds of formula (I) wherein X is oxygen. 41 WO 2006/135636 PCT/US2006/022142 Also, examples of preferred FTIs are those compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond. Another group of preferred FTIs are those compounds of formula (I) wherein R 1 is 5 hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , wherein Alk 1 is methylene and R 9 is C1 8alkylamino substituted with C1-6alkyloxycarbonyl. Still another group of preferred FTIs are those compounds of formula (I) wherein R 3 10 is hydrogen or halo; and R 2 is halo, C1-6alkyl, C2-6alkenyl, C1-6alkyloxy, trihalomethoxy or hydroxyC 1-6alkyloxy. A further group of preferred FTIs are those compounds of formula (I) wherein R 2 and

R

3 are on adjacent positions and taken together to form a bivalent radical of formula 15 (a-1), (a-2) or (a-3). A still further group of preferred FTIs are those compounds of formula (I) wherein R 5 is hydrogen and R 4 is hydrogen or C1-6alkyl. 20 Yet another group of preferred FTIs are those compounds of formula (I) wherein R 7 is hydrogen; and R 6 is C1-6alkyl or halo, preferably chloro, especially 4-chloro. Another exemplary group of preferred FTIs are those compounds of formula (I) wherein R 8 is hydrogen, hydroxy, haloCl-6alkyl, hydroxyC 1-6alkyl, cyanoC 1-6alkyl, 25 Cl-6alkyloxycarbonylC1-6alkyl, imidazolyl, or a radical of formula -NR 1 1

R

12 wherein R 1 1 is hydrogen or C12alky and.R12 ishydrogen,-C16alkyl; C1-6alkyloxy, hydroxy, C1-6alkyloxyCl-6alkylcarbonyl, or a radical of formula -Alk 2

-OR

13 wherein R 13 is hydrogen or C1-6alkyl. 42 WO 2006/135636 PCT/US2006/022142 Preferred compounds are also those compounds of formula (I) wherein R 1 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , wherein Alk 1 is methylene and R 9 is C1-8alkylamino substituted with C1-6alkyloxycarbonyl; R 2 is halo, C1-6alkyl, 5 C2-6alkenyl, C1-6alkyloxy, trihalomethoxy, hydroxyC1.6alkyloxy or Arl; R 3 is hydrogen; R 4 is methyl bound to the nitrogen in 3-position of the imidazole; R 5 is hydrogen; R 6 is chloro; R 7 is hydrogen; R 8 is hydrogen, hydroxy, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, imidazolyl, or a radical of formula -NR 1 1

R

12 wherein R 1 1 is hydrogen or Cl-12alkyl and R 12 is 10 hydrogen, C1-6alkyl, C1-6alkyloxy, C 1-6alkyloxyC 1-6alkylcarbonyl, or a radical of formula -Alk 2

-OR

13 wherein R 13 is C1-6alkyl; R 17 is hydrogen and R 18 is hydrogen. Especially preferred FTIs are: 15 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl- 1H-imidazol-5-yl)methyl] 1-methyl-2(1H)-quinolinone; 6-[amino(4-chlorophenyl)-l1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl) 1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)hydroxy(I-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl) 20 1-methyl-2(1H)-quinolinone; 6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1 methyl-2(1H)-quinolinone monohydrochloride.monohydrate; 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1 methyl-2(1IH)-quinolinone; 25 6-amino(4-chlorophenyl)(1-methyl- 1H-imidazol-5-yl)methyl]- 1-methyl-4-(3 propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a harmaceuticallyacceptable-acid-or-base-addition-salt-and (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3 chlorophenyl)-1-methyl-2(1H)-quinolinone (tipifarnib; Compound 75 in Table 1 of 30 WO 97/21701); and the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof. 43 WO 2006/135636 PCT/US2006/022142 Tipifarnib or ZARNESTRA ® is an especially preferred FTI. Further preferred FTIs include compounds of formula (IX) wherein one or more of the 5 following apply: * =XI-X 2

-X

3 is a trivalent radical of formula (x-l), (x-2), (x-3), (x-4) or (x-9) wherein each R 6 independently is hydrogen, C1- 4 alkyl, C1-4alkyloxycarbonyl, amino or aryl and R 7 is hydrogen; * >yly 2 _ is a trivalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each 10 R 9 independently is hydrogen, halo, carboxyl, C1 4 alkyl or Cl.4alkyloxycarbonyl; * ris 0, 1 or2; * sis 0 or 1; * tis 0; * R' is halo, CI- 6 alkyl or two R 1 substituents ortho to one another on the phenyl ring 15 may independently form together a bivalent radical of formula (a-1); * R 2 is halo; * R 3 is halo or a radical of formula (b-1) or (b-3) wherein 10 13

R

1 o is hydrogen or a radical of formula -Alk-OR 1 3

R

1 is hydrogen; 20 R 12 is hydrogen, C1- 6 alkyl, Cl- 6 alkylcarbonyl, hydroxy, C 1

-

6 alkyloxy or mono- or di(C1- 6 alkyl)aminoC 1

.

6 alkylcarbonyl; Alk is C_ 6 alkanediyl and R 13 is hydrogen; * R 4 is a radical of formula (c-1) or (c-2) wherein

R

16 is hydrogen, halo or mono- or di(C1- 4 alkyl)amino; 25 R 17 is hydrogen or C 1

-

6 alkyl; * aryl is phenyl. Another group of preferred FTIs are compounds of formula (IX) wherein =X 1

-X

2 X 3 -is -atrivalent-radical-offormulr (x--1, -(-2), (-3)-(x-bF4(-o-9JYY21-iY s a 30 trivalent radical of formula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R' is halo, C( 1 4 )alkyl or forms a bivalent radical of formula (a-1), R 2 is halo or C1- 4 alkyl, R 3 is hydrogen or a radical of formula (b-1) or (b-3), R 4 is a radical of formula (c-1) or (c 2), R 6 is hydrogen, C 1

-

4 alkyl or phenyl, R 7 is hydrogen, R 9 is hydrogen or C 1 4 alkyl, 44 WO 2006/135636 PCT/US2006/022142

R

1 0 is hydrogen or -Alk-OR" 3 , R" is hydrogen and R 1 2 is hydrogen or C 1 6 alkylcarbonyl and R 13 is hydrogen; Preferred FTIs are those compounds of formula (IX) wherein =X 1

-X

2

-X

3 is a trivalent 5 radical of formula (x-1) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-4), r is 0 or 1, s is 1, t is 0, R 1 is halo, preferably chloro and most preferably 3-chloro, R 2 is halo, preferably 4-chloro or 4-fluoro, R 3 is hydrogen or a radical of formula (b-1) or (b-3), R 4 is a radical of formula (c-1) or (c-2), R6 is hydrogen, R7 is hydrogen, R9 is hydrogen, R 1 0 is hydrogen, R" 1 is hydrogen and R 12 is hydrogen. 10 Other preferred FTIs are those compounds of formula (IX) wherein =X 1

-X

2

-X

3 is a trivalent radical of formula (x-2), (x-3) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R 1 is halo, preferably chloro, and most preferably 3-chloro or R' is C1- 4 alkyl, preferably 3-methyl, R 2 is halo, preferably 15 chloro, and most preferably 4-chloro, R 3 is a radical of formula (b-1) or (b-3), R 4 is a radical of formula (c-2), R 6 is C 14 alkyl, R 9 is hydrogen, R 1 0 and R 11 are hydrogen and R12 is hydrogen or hydroxy. Especially preferred FTI compounds of formula (IX) are: 20 7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[ 1,2-a]quinoline; a-(4-chlorophenyl)-a-(1-methyl- 1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline 7-methanol; 5-(3-chlorophenyl)-c-(4-chlorophenyl)-a-( 1-methyl- 1H-imidazol-5-yl)-imidazo[1,2 a]quinoline-7-methanol; 25 5-(3-chlorophenyl)-c-(4-chlorophenyl)-a-( 1-methyl-1H-imidazol-5-yl)imidazof[1,2 a]quinoline-7-methanamine; 5-(3-chlorophenyl)-a-(4-chlorophenyl)-a-(1-methyl-IH-imidazol-5-yl)tetrazolo[1,5 a]quinoline-7-methanamine; 5=(3=chlor-o-pheril)---(4-c e fiethyl-a-(1-methyl- 1H-imidazol-5-yl) 30 1,2,4-triazolo[4,3-a]quinoline-7-methanol; 5-(3-chlorophenyl)-a-(4-chlorophenyl)-(-( 1-methyl-1H-imidazol-5-yl)tetrazolo[1,5 a]quinoline-7-methanamine; 45 WO 2006/135636 PCT/US2006/022142 5-(3-chlorophenyl)-a-(4-chlorophenyl)-(-( 1-methyl-1H-imidazol-5-yl)tetrazolo[ 1,5 a]quinazoline-7-methanol; 5-(3-chlorophenyl)-a-(4-chlorophenyl)-4,5-dihydro-a-(1-methyl-l1H-imidazol-5 yl)tetrazolo[ 1,5-a]quinazoline-7-methanol; 5 5-(3-chlorophenyl)-oa-(4-chlorophenyl)-a-( 1-methyl- 1H-imidazol-5-yl)tetrazolo[ 1,5 a]quinazoline-7-methanamine; 5-(3-chlorophenyl)-a-(4-chlorophenyl)-N-hydroxy-aX-(1-methyl- 1H-imidazol-5 yl)tetrahydro[ 1,5-a]quinoline-7-methanamine; and a-(4-chlorophenyl)-a-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[ 1,5 10 a]quinoline-7-methanamine; and the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof. 5-(3-chlorophenyl)-(x-(4-chlorophenyl)-ac-( 1-methyl-1H-imidazol-5-yI)tetrazolo[ 1,5 a]quinazoline-7-methanamine, especially the (-) enantiomer, and its pharmaceutically 15 acceptable acid addition salts is an especially preferred FTI. The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the FTI compounds of formulas (I), (II), (III), (IV), (V), 20 (VI), (VII), (VIII) or (IX) are able to form. The FTI compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Appropriate acids include, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; 25 phosphoric and the like acids; or organic acids, such as acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and 30 The FTI compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating the acid form with a suitable organic or inorganic base. 46 WO 2006/135636 PCT/US2006/022142 Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D glucamine, hydrabamine salts, and salts with amino acids, for example, arginine, 5 lysine and the like. Acid and base addition salts also comprise the hydrates and the solvent addition forms which the preferred FTI compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) are able to form. Examples of such forms are e.g. hydrates, alcoholates 10 and the like. The FTI compounds of formulae (I), (II), (III), (IV); (V), (VI), (VII), (VIII) or (IX), as used hereinbefore, encompass all stereochemically isomeric forms of the depicted structural formulae (all possible compounds made up of the same atoms bonded by 15 the same sequence of bonds but having different three-dimensional structures that are not interchangeable). Unless otherwise mentioned or indicated, the chemical designation of an FTI compound should be understood as encompassing the mixture of all possible stereochemically isomeric forms which the compound may possess. Such mixture may contain all diastereomers and/or enantiomers of the basic 20 molecular structure of the compound. All stereochemically isomeric forms of the FTI compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) both in pure form or in admixture with each other are intended to be embraced within the scope of the depicted formulae. 25 Some of the FTI compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) may also exist in their tautomeric forms. Such forms, although not explicitly shown in the above formulae, are intended to be included within the scope thereof. Thus,-unless-i4ndicated-otherwise-hereinafter,-theterrns-"compofdind6ff6irmulae (I), 30 (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX)" and "farnesyltransferase inhibitors of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX)" are meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric and tautomeric forms. 47 WO 2006/135636 PCT/US2006/022142 Other farnesyltransferase inhibitors which can be employed in accordance with the present invention include: Arglabin, perrilyl alcohol, SCH-66336, 2(S)-[2(S)-[2(R) amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl 5 methionine sulfone (Merck); L778123, BMS 214662, Pfizer compounds A and B described above. Suitable dosages or therapeutically effective amounts for the compounds Arglabin (WO98/28303), perrilyl alcohol (WO 99/45712), SCH-66336 (US 5,874,442), L778123 (WO 00/01691), 2(S)-[2(S)-[2(R)-amino-3 mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine 10 sulfone (WO94/10138), BMS 214662 (WO 97/30992), Pfizer compounds A and B (WO 00/12499 and WO 00/12498) are given in the published patent specifications or are known to or can be readily determined by a person skilled in the art. 15 FLT3 KINASE INHIBITORS The FLT3 kinase inhibitors of the present invention comprise compounds Formula I': B

R

3 Z ' N-.3 ) q N O Q X

R

2 ') N Fonnrmula I' 20 and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis0, 1 or2; p is 0 or 1; 25 Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; 48 WO 2006/135636 PCT/US2006/022142 B is selected from: cycloalkyl (wherein said cycloalkyl is preferably cyclopentanyl, cyclohexanyl, cyclopentenyl or cyclohexenyl), a nine to ten membered benzo-fused heteroaryl (wherein said nine to ten membered benzo-fused heteroaryl is preferably benzothiazolyl, benzooxazolyl, benzoimidazolyl, benzofuranyl, indolyl, quinolinyl, 5 isoquinolinyl, or benzo[b]thiophenyl), or a nine to ten membered benzo-fused heterocyclyl (wherein said nine to ten membered benzo-fused heterocyclyl is preferably 2,3-dihydro-benzothiazolyl, 2,3-dihydro-benzooxazolyl, 2,3-dihydro-benzoimidazolyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, isochromanyl, 2,3-dihydro-indolyl, 10 2,3-dihydro-benzofuranyl or 2,3-dihydro-benzo[b]thiophenyl, and most preferably 2,3-dihydro-indolyl, 2,3-dihydro-benzofuranyl or 2,3-dihydro-benzo[b]thiophenyl), or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl, (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, 15 or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl);

R

1 and R2 are independently selected from the following: Y nRa / nRa , Ran Ra -Rbb n ' n (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; 20 Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, triazolyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, 25 thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, triazolyl, or pyrazinyl), hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted-with-Rs 5 ,-pyrrolidinonyl-optioally-SiliuiiittFdwit-Rk5, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with R 5 (wherein said 30 heterocyclyl is preferably pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, 49 WO 2006/135636 PCT/US2006/022142 tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, or piperazinyl), squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, 5 -OSO 2 NRwRx, or -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, triazolyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, 10 thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, triazolyl, or pyrazinyl), or heterocyclyl (wherein said heterocyclyl is preferably pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, or 15 piperazinyl); Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C( 1 -4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl 20 (wherein the aryl portion of said aralkyl is preferrably phenyl), or heteroaralkyl (wherein the heteroaryl portion of said heteroaralkyl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, 25 imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl), or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO2, or S, preferably selected from the group consisting of: 'NC N 'N 'N , 0 , O S, N(alkyl ) 'N 'N 30 K~.NH, and 50 WO 2006/135636 PCT/US2006/022142 Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl (wherein said cycloalkyl is preferably cyclopentanyl or cyclohexanyl), phenyl, aralkyl (wherein the aryl portion of said aralkyl is preferably phenyl), heteroaralkyl 5 (wherein the heteroaryl portion of said heteroaralkyl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl), or heteroaryl (wherein said heteroaryl is 10 preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most preferably pyrrolyl, furanyl, thiophenyl, imnidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl); and

R

3 is one or more substituents, optionally present, and independently selected from: 15 alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 (wherein said cycloalkyl is preferably cyclopentanyl or cyclohexanyl), heteroaryl optionally substituted with R 4 (wherein said heteroaryl is preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, triazolyl, pyrazinyl, pyridinyl-N-oxide, or pyrrolyl-N-oxide, and most 20 preferably pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, triazolyl, or pyrazinyl), alkylamino, heterocyclyl optionally substituted with R 4 (wherein said heterocyclyl is preferably azepenyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, thiomorpholinyl, morpholinyl, 25 or piperazinyl tetrahydropyridinyl. tetrahydropyrazinyl, dihydrofuranyl, dihydrooxazinyl, dihydropyrrolyl, or dihydroimidazolyl), alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy QptionallysubstitutedcLwithR 4 ,. dialk-ylamino,- -NtIS O2alkyl-or--SO 2 alkyl,- wherein 30 R 4 is independently selected from halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. 51 WO 2006/135636 PCT/US2006/022142 As used hereafter, the term "compounds of Formula I' "is meant to include also the N-oxides, pharmaceutically acceptable salts, solvates, and stereochemical isomers thereof. 5 FLT3 inhibitors of Formula I' - Abbreviations & Definitions As used in regards to the FLT3 inhibitors of Formula I', the following terms are intended to have the following meanings: 10 ATP adenosine triphosphate Boc tert-butoxycarbonyl DCM dichloromethane DMF dimethylformamide DMSO dimethylsulfoxide 15 DIEA diisopropylethylamine DTT dithiothreitol EDC 1-(3-dimethylamninopropyl)-3-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraaceticacid EtOAc ethyl acetate 20 FBS fetal bovine serum FP fluorescence polarization GM-CSF granulocyte and macrophage colony stimulating factor HBTU O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate 25 Hex hexane HOBT 1-hydroxybenzotriazole hydrate HPBCD hydroxypropyl B-cyclodextrin HRP horseradish peroxidase i-PrOH isopropyl alcohol 30 LC/MS (ESI) Liquid chromatography/mass spectrum (electrospray ionization) MeOH Methyl alcohol NMM N-methylmorpholine NMR nuclear magnetic resonance 35 PS polystyrene PBS phosphate buffered saline RPMI Rosewell Park Memorial Institute RT room temperature RTK receptor tyrosine kinase 40 NaHMDS sodium hexamethyldisilazane SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoreisis TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran 45 TLC thin layer chromatography 52 WO 2006/135636 PCT/US2006/022142 (Additional abbreviations are provided where needed throughout the Specification.) DEFINITIONS 5 As used in regards to the FLT3 inhibitors of Formula I', the following terms are intended to have the following meanings (additional definitions are provided where needed throughout the Specification): 10 The term "alkenyl," whether used alone or as part of a substituent group, for example,

"C

1

-

4 alkenyl(aryl)," refers to a partially unsaturated branched or straight chain monovalent hydrocarbon radical having at least one carbon-carbon double bond, whereby the double bond is derived by the removal of one hydrogen atom from each of two adjacent carbon atoms of a parent alkyl molecule and the radical is derived by 15 the removal of one hydrogen atom from a single carbon atom. Atoms may be oriented about the double bond in either the cis (Z) or trans (E) conformation. Typical alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl (2 propenyl), butenyl and the like. Examples include C 2 -8alkenyl or C 2

-

4 alkenyl groups. 20 The term "Ca-b" (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, C1- 4 denotes a radical containing 1, 2, 3 or 4 carbon atoms. 25 The term "alkyl," whether used alone or as part of a substituent group, refers to a saturated branched or straight chain monovalent hydrocarbon radical, wherein the radical is derived by the removal of one hydrogen atom from a single carbon atom. UJnless-specifical-y-indicated(e.-g.-by -the-use ofa-limiting-ternrsuhas-"tiermi-t 30 carbon atom"), substituent variables may be placed on any carbon chain atom. Typical alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl and the like. Examples include CI-salkyl, C1- 6 alkyl and C1- 4 alkyl groups. 53 WO 2006/135636 PCT/US2006/022142 The term "alkylamino" refers to a radical formed by the removal of one hydrogen atom from the nitrogen of an alkylamine, such as butylamine, and the term "dialkylamino" refers to a radical formed by the removal of one hydrogen atom from the nitrogen of a secondary amine, such as dibutylamine. In both cases it is expected 5 that the point of attachment to the rest of the molecule is the nitrogen atom. The term "alkynyl," whether used alone or as part of a substituent group, refers to a partially unsaturated branched or straight chain monovalent hydrocarbon radical having at least one carbon-carbon triple bond, whereby the triple bond is derived by 10 the removal of two hydrogen atoms from each of two adjacent carbon atoms of a parent alkyl molecule and the radical is derived by the removal of one hydrogen atom from a single carbon atom. Typical alkynyl radicals include ethynyl, propynyl, butynyl and the like. Examples include C 2 -salkynyl or C 2

.

4 alkynyl groups. 15 The term "alkoxy" refers to a saturated or partially unsaturated branched or straight chain monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen substituent on a parent alkane, alkene or alkyne. Where specific levels of saturation are intended, the nomenclature "alkoxy", "alkenyloxy" and "alkynyloxy" are used consistent with the definitions of alkyl, 20 alkenyl and alkynyl. Examples include Ci-salkoxy or CxI.

4 alkoxy groups. The term "alkoxyether" refers to a saturated branched or straight chain monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen substituent on a hydroxyether. Examples include 1-hydroxyl-2 25 methoxy-ethane and 1-(2-hydroxyl-ethoxy)-2-methoxy-ethane groups. The term "aralkyl" refers to a C 1 i 6 alkyl group containing an aryl substituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl. It is intended that the point of-attachment-to-the-rest-of-the-molecule-be-the-alkyl-group. 30 The term "aromatic" refers to a cyclic hydrocarbon ring system having an unsaturated, conjugated 7r electron system. 54 WO 2006/135636 PCT/US2006/022142 The term "aryl" refers to an aromatic cyclic hydrocarbon ring radical derived by the removal of one hydrogen atom from a single carbon atom of the ring system. Typical aryl radicals include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, anthracenyl and the like. 5 The term "arylamino" refers to an amino group, such as ammonia, substituted with an aryl group, such as phenyl. It is expected that the point of attachment to the rest of the molecule is through the nitrogen atom. 10 The term "benzo-fused cycloalkyl" refers to a bicyclic fused ring system radical wherein one of the rings is phenyl and the other is a cycloalkyl or cycloalkenyl ring. Typical benzo-fused cycloalkyl radicals include indanyl, 1,2,3,4-tetrahydro naphthalenyl, 6,7,8,9,-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro benzocyclooctenyl and the like. A benzo-fused cycloalkyl ring system is a subset of 15 the aryl group. The term "benzo-fused heteroaryl" refers to a bicyclic fused ring system radical wherein one of the rings is phenyl and the other is a heteroaryl ring. Typical benzo fused heteroaryl radicals include indolyl, indolinyl, isoindolyl, benzo[b]furyl, 20 benzo[b]thienyl, indazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, and the like. A benzo-fused heteroaryl ring is a subset of the heteroaryl group. The term "benzo-fused heterocyclyl" refers to a bicyclic fused ring system radical 25 wherein one of the rings is phenyl and the other is a heterocyclyl ring. Typical benzo fused heterocyclyl radicals include 1,3-benzodioxolyl (also known as 1,3 methylenedioxyphenyl), 2,3-dihydro-1,4-benzodioxinyl (also known as 1,4 ethylenedioxyphenyl), benzo-dihydro-furyl, benzo-tetrahydro-pyranyl, benzo dihydro-thienyl-and-the-like.

30 The term "carboxyalkyl" refers to an alkylated carboxy group such as tert butoxycarbonyl, in which the point of attachment to the rest of the molecule is the carbonyl group. 55 WO 2006/135636 PCT/US2006/022142 The term "cyclic heterodionyl" refers to a heterocyclic compound bearing two carbonyl substituents. Examples include thiazolidinyl diones, oxazolidinyl diones and pyrrolidinyl diones. 5 The term "cycloalkenyl" refers to a partially unsaturated cycloalkyl radical derived by the removal of one hydrogen atom from a hydrocarbon ring system that contains at least one carbon-carbon double bond. Examples include cyclohexenyl, cyclopentenyl and 1,2,5,6-cyclooctadienyl. 10 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon ring radical derived by the removal of one hydrogen atom from a single ring carbon atom. Typical cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and 15 cyclooctyl. Additional examples include C 3 -8cycloalkyl, Cs_8cycloalkyl,

C

3 -1 2 cycloalkyl, C 3 -20cycloalkyl, decahydronaphthalenyl, and 2,3,4,5,6,7-hexahydro 1H-indenyl. The term "fused ring system" refers to a bicyclic molecule in which two adjacent 20 atoms are present in each of the two cyclic moieties. Heteroatoms may optionally be present. Examples include benzothiazole, 1,3-benzodioxole and decahydronaphthalene. The term "hetero" used as a prefix for a ring system refers to the replacement of at 25 least one ring carbon atom with one or more atoms independently selected from N, S, O or P. Examples include rings wherein 1, 2, 3 or 4 ring members are a nitrogen atom; or, 0, 1, 2 or 3 ring members are nitrogen atoms and 1 member is an oxygen or sulfur atom. 30 The term "heteroaralkyl" refers to a C1- 6 alkyl group containing a heteroaryl substituent. Examples include furylmethyl and pyridylpropyl. It is intended that the point of attachment to the rest of the molecule be the alkyl group. 56 WO 2006/135636 PCT/US2006/022142 The term "heteroaryl" refers to a radical derived by the removal of one hydrogen atom from a ring carbon atom of a heteroaromatic ring system. Typical heteroaryl radicals include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, 5 pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8 naphthyridinyl, pteridinyl and the like. 10 The term "heteroaryl-fused cycloalkyl" refers to a bicyclic fused ring system radical wherein one of the rings is cycloalkyl and the other is heteroaryl. Typical heteroaryl fused cycloalkyl radicals include 5,6,7,8-tetrahydro-4H-cyclohepta(b)thienyl, 5,6,7 trihydro-4H-cyclohexa(b)thienyl, 5,6-dihydro-4H-cyclopenta(b)thienyl and the like. 15 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic ring radical derived by the removal of one hydrogen atom from a single carbon or nitrogen ring atom. Typical heterocyclyl radicals include 2H-pyrrolyl, 2-pyrrolinyl, 3 pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2-imidazolinyl (also referred to as 4,5 dihydro-lH-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, tetrazolyl, 20 piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, azepanyl, hexahydro-1,4-diazepinyl and the like. The term "squaryl" refers to a cyclobutenyl 1,2 dione radical. 25 The term "substituted," refers to a core molecule on which one or more hydrogen atoms have been replaced with one or more functional radical moieties. Substitution is not limited to a core molecule, but may also occur on a substituent radical, whereby the substituent radical becomes a linking group. 30 The term "independently selected" refers to one or more substituents selected from a group of substituents, wherein the substituents may be the same or different. 57 WO 2006/135636 PCT/US2006/022142 The substituent nomenclature used in the disclosure of the FLT3 inhibitors of Formula I' was derived by first indicating the atom having the point of attachment, followed by the linking group atoms toward the terminal chain atom from left to right, substantially as in: 5 (Cl_ 6 )alkylC(O)NH(C 1

.

6 )alkyl(Ph) or by first indicating the terminal chain atom, followed by the linking group atoms toward the atom having the point of attachment, substantially as in: 10 Ph(C 1

-

6 )alkylamido(C 1

-

6 )alkyl either of which refers to a radical of the formula: 0

-C

1 CC /, alky C- -CC alkyA N -C-( y -Q H 15 Additionally, lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms. When any variable (e.g. R 4 ) occurs more than one time in any embodiment of the FLT3 inhibitors of Formula I', each definition is intended to be independent. 20 EMBODIMENTS OF FLT3 INHIBITORS OF FORMULA I' In an embodiment of the FLT3 inhibitors of Formula I': N-oxides are optionally 25 present on one or more of: N-1 or N-3 (when X is N) (see Figure 1 below for ring numbers). Figure-1 58 WO 2006/135636 PCT/US2006/022142 B Rs Z N 5 4

R

1 6 R9 7 N 2 8 1 Figure 1 illustrates ring atoms numbered 1 through 8, as used in the present specification. 5 Preferred embodiments of the the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: q is 0, 1 or 2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; 10 X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: a nine to ten membered benzo-fused heteroaryl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl;

R

1 and R 2 are independently selected from the following: 15 YRa f ~R, n SY a a a Ra -l-Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) . wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, 20 alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, 59 WO 2006/135636 PCT/US2006/022142 -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or

-SO

2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from: halogen, 5 cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C( 1

-

4 )alkyl-OH, or alkylamino; Rw and R, are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and R,, may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, 10 N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and

R

3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with 15 R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R4, -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein

R

4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, 20 alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. Other preferred embodiments of the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: qis0, 1 or2; 25 p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; 30 R 1 and R 2 are independently selected from the following: 60 WO 2006/135636 PCT/US2006/022142 Ya Rabn nn

Y

R a R Ra R a Ra -- Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) . wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, 5 alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R 5 , pyrrolidinonyl optionally substituted with R 5 , piperidinonyl optionally substituted with R 5 , cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, 10 -SRy, -SORy, -SO 2 Ry, -NRwS0 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or

-SO

2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, 15 -C(O)N(alkyl) 2 , alkyl, -C(1.4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; 20 Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and

R

3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R4, alkoxyether, -O(cycloalkyl), 25 phenoxy optionally substituted with R 4 , or dialkylamino; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl,

=CO

2 alkyl,- -SO 2 alk-yl C(O)N(alkyl) 2 , alkyl, or -alkyffuno. Still other preferred embodiments of the FLT3 inhibitors of Formula I' are 30 compounds of Formula I' wherein one or more of the following limitations are present: 61 WO 2006/135636 PCT/US2006/022142 qis 0, 1 or2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; 5 Z is NH, N(alkyl), or CH 2 ; B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; R, and 112 are independently selected from the following: SY Ra / Ra n Ra "R a -- Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) 10 wherein n is 1, 2, 3 or 4; Y is a direct bond, O, NH, or N(alkyl); Ra is alkoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, heterocyclyl 15 optionally substituted with Rs, -CONRwRx, -N(Ry)CON(Rw)(Rx), -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, or -NRwSO 2 Ry; Rbb is hydrogen, halogen or alkoxy; Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, 20 -C(0)N(alkyl) 2 , alkyl, -C( 1 .4)alkyl-OH, or alkylamino; Rw and R, are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and R, may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; 25 Ry, is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and R3-is.one-or-more-substituents-independently-selected-from:-akyl-;-alkoxy,-halogen;, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), 30 phenoxy optionally substituted with R 4 , or dialkylamino; wherein R4 is independently 62 WO 2006/135636 PCT/US2006/022142 selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl,

-CO

2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. Particularly preferred embodiments of the FLT3 inhibitors of Formula I' are 5 compounds of Formula I' wherein one or more of the following limitations are present: qis 0, 1 or2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; 10 Z is NH or CH 2 ; B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen;

R

1 and R 2 are independently selected from the following: -Y'nRa n Ra -1-Rbb (a-1), (a-4), or (a-5) 15 wherein n is 1, 2, or 3; Y is O; Ra is alkoxy, hydroxyl, heteroaryl optionally substituted with Rs, alkylamino, dialkylamino, pyrrolidinonyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, -CONRwRx, -N(Ry)CON(Rw)(Rx), -S0 2 Ry, or 20 -NRwS0 2 Ry; Rbb is hydrogen, halogen, or alkoxy; Rs is one substituent independently selected from: -C(0)alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, or -C( 1

-

4 )alkyl-OH; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, 25 or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N_(alkyl),SO,.SO 2 ,-or-S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 30 R 3 is one substituent selected from: alkyl, alkoxy, cycloalkyl, heterocyclyl, -O(cycloalkyl), phenoxy, or dialkylamino. 63 WO 2006/135636 PCT/US2006/022142 Most particularly preferred embodiments of the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: 5 q is 1 or 2; p is 0 or 1; Q is NH, O, or a direct bond; X is N; Z is NH; 10 B is selected from: phenyl and pyridinyl;

R

1 and R 2 are independently selected from the following: Y Ra, -j-Rbb (a-1), or (a-5) 15 wherein n is 1, 2, or 3; Y is O; Ra is alkoxy, hydroxyl, alkylamino, dialkylamino, pyrrolidinonyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, or -NRwSO 2 Ry; 20 Rbb is hydrogen or alkoxy; Rs is one substituent independently selected from: -C(O)alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, or -C(I-4)alkyl-OH; Rw and R,, are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 25 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cylcoalkyl,.phenyl,aralkyl, heteroaralkyl, or heteroaryl; and

R

3 is one substituent selected from: alkyl, alkoxy, heterocyclyl, -O(cycloalkyl), or 30 dialkylamino. 64 WO 2006/135636 PCT/US2006/022142 Preferred embodiments of the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: qis 0, 1 or2; p is 0 or 1; 5 Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: a nine to ten membered benzo-fused heteroaryl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; 10 one of R 1 and R 2 is H, and the other is independently selected from the following: Zx Y( Ra jRa R a Ra n Ra (a-1), (a-2), (a-3), or (a-4) wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); 15 Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with R 5 , piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with R 5 , heterocyclyl optionally substituted with R 5 , squaryl, -COORy, -CONRwRx, 20 -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(0)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OS0 2 NRwRx, or

-SO

2 NRwRx; Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, 25 -C(0)N(alkyl) 2 , alkyl, -C(1-4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO2, or S; 30 Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 65 WO 2006/135636 PCT/US2006/022142

R

3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with

R

4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally 5 substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein

R

4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. 10 Other preferred embodiments of the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: q is 0, 1 or 2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; 15 X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; one of R, and R 2 is H, and the other is independently selected from the following: Y Ra - Ra ,, Ra Ra n Ra (a-1), (a-2), (a-3), or (a-4) 20 wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally 25 substituted with Rs, cyclic heterodionyl optionally substituted with R 5 , heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx) -N(Ry)CQN(R)(Rx),-- N(Rw)C(O)ORx,--N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OS0 2 NRwRx, or

-SO

2 NRwRx; 66 WO 2006/135636 PCT/US2006/022142 Rs is one, two, or three substituents independently selected from halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C( 1 -4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, 5 or heteroaralkyl, or Rw and R,, may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 10 R 3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), phenoxy optionally substituted with R 4 , or dialkylamino; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, 15 -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. Still other preferred embodiments of the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: 20 q is 0, 1 or 2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; 25 B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; one of R 1 and R 2 is H, and the other is independently selected from the following: >~ Ra f Ra r>Ra Ra nn (a-1), (a-2), (a-3), or (a-4) herin-n is 1, 2, 3 or 4; Y is a direct bond, O, NH, or N(alkyl); 30 Ra is alkoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, heterocyclyl 67 WO 2006/135636 PCT/US2006/022142 optionally substituted with Rs, -CONRwRx, -N(Ry)CON(Rw)(Rx), -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, or -NRwSO 2 Ry; Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, 5 -C(O)N(alkyl) 2 , alkyl, -C(-4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; 10 Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and

R

3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), 15 phenoxy optionally substituted with R 4 , or dialkylamino; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl,

-CO

2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. Particularly preferred embodiments of the FLT3 inhibitors of Formula I' are 20 compounds of Formula I' wherein one or more of the following limitations are present: qis0, 1 or2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; 25 Z is NH or CH 2 ; B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; one of R, and R 2 is H, and the other is independently selected from the following: XIYR- ;W Ra n (a-1), or (a-4) 30 wherein n is 1, 2, or 3; Y is O; 68 WO 2006/135636 PCT/US2006/022142 Ra is alkoxy, hydroxyl, heteroaryl optionally substituted with Rs, alkylamino, dialkylamino, pyrrolidinonyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, -CONRwRx, -N(Ry)CON(Rw)(Rx), -SO 2 Ry, or -NRwSO 2 Ry; 5 Rs is one substituent independently selected from: -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or -C(I.4)alkyl-OH; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, 10 N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and

R

3 is one substituent selected from: alkyl, alkoxy, cycloalkyl, heterocyclyl, -O(cycloalkyl), phenoxy, or dialkylamino. 15 Most particularly preferred embodiments of the FLT3 inhibitors of Formula I' are compounds of Formula I' wherein one or more of the following limitations are present: q is 1 or 2; 20 p is 0 or 1; Q is NH, O, or a direct bond; X is N; Z is NH; B is selected from: phenyl and pyridinyl; 25 one of R 1 and R 2 is H, and the other is independently selected from the following: . , Y'nRa (a-1) wherein- is-,2, ri-3; Y is O; 30 Ra is alkoxy, hydroxyl, alkylamino, dialkylamino, pyrrolidinonyl optionally substituted with Rs, heterocyclyl optionally substituted with R 5 , or -NRwSO 2 Ry; 69 WO 2006/135636 PCT/US2006/022142 Rs is one substituent independently selected from: -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or -C( 1

.-

4 )alkyl-OH; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 5 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 1R3 is one substituent selected from: alkyl, alkoxy, heterocyclyl, -O(cycloalkyl), or 10 dialkylamino. The FLT3 inhibitors of Formula I' may also be present in the form of pharmaceutically acceptable salts. 15 For use in medicines, the salts of the compounds of the FLT3 inhibitors of Formula I' refer to non-toxic "pharmaceutically acceptable salts." FDA approved pharmaceutically acceptable salt forms (Ref International J. Pharm. 1986, 33, 201 217; J. Pharm. Sci., 1977, Jan, 66(1), pl) include pharmaceutically acceptable acidic/anionic or basic/cationic salts. 20 Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, 25 hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. 30 Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, saccharinic or trifluoroacetic acid. 70 WO 2006/135636 PCT/US2006/022142 Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or "TRIS"), ammonia, benzathine, 5 t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH 3 , NH40H, N-methyl-D-glucamine, piperidine, potassium, potassium-t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, 10 sodium-2-ethylhexanoate (SEH), sodium hydroxide, triethanolamine (TEA) or zinc. The FLT3 inhibitors of the present invention includes within its scope prodrugs of the compounds of Formula I'. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into an active compound. Thus, 15 in the methods of treatment of the present invention, the term "administering" shall encompass the means for treating, ameliorating or preventing a syndrome, disorder or disease described herein with a FLT3 inhibitor of Formula I' specifically disclosed or a compound, or prodrug thereof, which would obviously be included within the scope of the invention albeit not specifically disclosed for certain of the instant compounds. 20 Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in, for example, "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. One skilled in the art will recognize that the FLT3 inhibitors of Formula I' may have 25 one or more asymmetric carbon atoms in their structure. It is intended that the present invention include within its scope single enantiomer forms of the FLT3 inhibitors of Formula I', racemic mixtures, and mixtures of enantiomers in which an enantiomeric excess is present. 30 The term "single enantiomer" as used herein defines all the possible homochiral forms which the compounds of Formula I and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. 71 WO 2006/135636 PCT/US2006/022142 Stereochemically pure isomeric forms may be obtained by the application of art known principles. Diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the 5 diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereoselective reactions. The term "isomer" refers to compounds that have the same composition and 10 molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or in an ability to rotate the plane of polarized light (enantiomers). 15 The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "chiral" refers to the structural characteristic of a molecule that makes it 20 impossible to superimpose it on its mirror image. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. 25 The term "diastereomer" refers to stereoisomers that are not mirror images. The symbols "R" and "S" represent the configuration of substituents around a chiral carbon atom(s). 30 The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity. 72 WO 2006/135636 PCT/US2006/022142 The term "homochiral" refers to a state of enantiomeric purity. The term "optical activity" refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light. 5 The term "geometric isomer" refers to isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring or to a bridged bicyclic system. Substituent atoms (other than H) on each side of a carbon-carbon double bond may be in an E or Z configuration. In the "E" (opposite 10 sided) configuration, the substituents are on opposite sides in relationship to the carbon- carbon double bond; in the "Z" (same sided) configuration, the substituents are oriented on the same side in relationship to the carbon-carbon double bond. Substituent atoms (other than hydrogen) attached to a carbocyclic ring may be in a cis or trans configuration. In the "cis" configuration, the substituents are on the same side 15 in relationship to the plane of the ring; in the "trans" configuration, the substituents are on opposite sides in relationship to the plane of the ring. Compounds having a mixture of "cis" and "trans" species are designated "cis/trans". It is to be understood that the various substituent stereoisomers, geometric isomers 20 and mixtures thereof used to prepare compounds of the present invention are either commercially available, can be prepared synthetically from commercially available starting materials or can be prepared as isomeric mixtures and then obtained as resolved isomers using techniques well-known to those of ordinary skill in the art. 25 The isomeric descriptors "R," "S," "E," "Z," "cis," and "trans" are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations for Fundamental Stereochemistry (Section E), Pure Appl. Chemn., 1976, 45:13-30). 30 The FLT3 inhibitors of Formula I' may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the free base of each isomer of an isomeric pair using an optically active salt (followed by fractional crystallization and regeneration 73 WO 2006/135636 PCT/US2006/022142 of the free base), forming an ester or amide of each of the isomers of an isomeric pair (followed by chromatographic separation and removal of the chiral auxiliary) or resolving an isomeric mixture of either a starting material or a final product using preparative TLC (thin layer chromatography) or a chiral HPLC column. 5 Furthermore, the FLT3 inhibitors of Formula I' may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention. In addition, some of the FLT3 inhibitors of Formula I' may form solvates, for example with water (i.e., hydrates) or common organic solvents. As used 10 herein, the term "solvate" means a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 15 The term "solvate" is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. It is intended that the present invention include within its scope solvates of the FLT3 20 inhibitors of Formula I' of the present invention. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the means for treating, ameliorating or preventing a syndrome, disorder or disease described herein with a FLT3 inhibitor of Formula I' specifically disclosed or a compound, or solvate thereof, which would obviously be included within the scope of the invention albeit 25 not specifically disclosed for certain of the instant compounds. The FLT3 inhibitors of Formula I' may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N -oxide-form:-Said-N=oxidation reactionmnfay-geardryallI-b carfi-eut- byft-li ~iftig tie 30 starting material of Formula I' with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, 74 WO 2006/135636 PCT/US2006/022142 benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3 chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alky1hydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, 5 e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents. Some of FLT3 inhibitors of Formula I' may also exist in their tautomeric forms. Such forms although not explicitly indicated in the present application are intended to be 10 included within the scope of the present invention. PREPARATION OF FLT3 INHIBITORS OF FORMULA I' 15 During any of the processes for preparation of the FLT3 inhibitors of Formula I', it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protecting Groups, P. Kocienski, Thieme Medical Publishers, 2000; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic 20 Synthesis, 3 rd ed. Wiley Interscience, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. FLT3 inhibitors of Formula I' can be prepared by methods known to those who are skilled in the art. The following reaction schemes are only meant to represent 25 examples of the invention and are in no way meant to be a limit of the invention. General Reaction Scheme 75 WO 2006/135636 PCT/US2006/022142 B Ra' OL" N )q Z IR FLT3 inhibitors of Formula I' can be prepared by methods known to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention. 5 The FLT3 inhibitors of Formula I', wherein Q is O and p, q, B, X, Z, R 1 , R 2 , and R 3 are as defined in Formula I', may be synthesized as outlined by the general synthetic route illustrated in Scheme 1. Treatment of an appropriate 4-chloroquinazoline or quinoline II' with an appropriate hydroxy cyclic amine III' in a solvent such as 10 isopropanol at a temperature of 50 'C to 150 oC can provide the intermediate IV'. Treatment of intermediate IV' with a base such as sodium hydride in a solvent such as tetrahydrofuran (THF) followed by addition of the appropriate acylating group V', wherein Z is NH or N(alkyl) and LG may be chloride, p-nitrophenoxy or imidazole, or, when Z is CH 2 , via coupling with an appropriate R 3

BCH

2

CO

2 H using a standard 15 coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT), can provide the final product I'. The 4-chloroquinazolines or quinolines II' are either commercially available or can be prepared as outlined in Schemes 6 or 7; the hydroxy cyclic amines III' are commercially available or are derived from known methods (JOC, 1961, 26, 20 1519; EP314362). The acylating reagents V' are either commercially available or can be prepared as illustrated in Scheme 1. Treatment of an appropriate R 3 BZH, wherein Z is NH or N(alkyl), with an appropriate acylating reagent such as carbonyldiimidazole or p-nitrophenylchloroformate in the presence.oflabase.such-as triethylamine can provide V'. Many R 3 BZH reagents are either commercially 25 available and can be prepared by a number of known methods (e.g.Tet Lett 1995, 36, 2411-2414). 76 WO 2006/135636 PCT/US2006/022142 Scheme 1 B Z Rs HQ HQ )O

R

3

OQ

7 ) R1 H Rl, ' x 0 L X II R 2 LV ' / b a s e R 1 X R2 N" N or ~ ~ I IV' B R 2 N, LG is a leaving group O O 0 -OH /Coupling Reagent B LG LG ZR3 HZ

R

3 base O ,LG V' Alternatively FLT3 inhibitors of Formula I', wherein Q is O, Z is NH or N(alkyl), and p, q, B, X, R 1 , R 2 , and R 3 are defined as in Formula I', may be synthesized as outlined 5 by the general synthetic route illustrated in Scheme 2. Treatment of alcohol intermediate IV', prepared as described in Scheme 1, with an acylating agent such as carbonyldiimidazole or p-nitrophenylchloroformate, wherein LG may be chloride, imidazole, or p-nitrophenoxy, can provide the acylated intermediate VI'. Subsequent treatment of VI' with an appropriate R 3 BZH, wherein Z is NH or N(alkyl), can 10 provide the final product I'. The acylating reagents are commercially available while many R 3 BZH reagents are either commercially available and can be prepared by a number of known methods (e.g.Tet Lett 1995, 36, 2411-2414). Scheme 2ZR3 B O Z R Q LG Q 7 O--Q N 0 N BN~ . N LG6 G RR HZ R 3 RR -- base--

R

2 N -base-N IV' VI' It wherein LG is a leaving group 77 WO 2006/135636 PCT/US2006/022142 An alternative method to prepare FLT3 inhibitors of Formula I', wherein Q is O, Z is NH, and p, q, B, X, R 1 , R 2 , and R 3 are defined as in Formula I', is illustrated in Scheme 3. Treatment of alcohol intermediate IV', prepared as described in Scheme 1, with an appropriate isocyanate in the presence of a base such as triethylamine can 5 provide the final product I'. The isocyanates are either commercially available or can be prepared by a known method (J. Org Chem, 1985, 50, 5879-5881). Scheme 3 HN R 3 HQO Q P N B R OCN R 3 X base R IV' I 10 A method for preparing FLT3 inhibitors of Formula I', wherein Q is NH or N(alkyl), and p, q, B, X, Z, R 1 , R 2 , and R 3 are defined as in Formula I', is outlined by the general synthetic route illustrated in Scheme 4. Treatment of the appropriate chloroquinazoline or quinoline II' with an N-protected aminocyclic amine VII', where PG is an amino protecting group known to those skilled in the art, in a solvent 15 such as isopropanol at a temperature of 50 oC to 150 oC can provide intermediate VIII'. Deprotection of the amino protecting group (PG) under standard conditions known in the art can provide compound IX', which can then be acylated with an appropriate reagent V', wherein Z is NH or N(alkyl) and LG may be chloride, p nitrophenoxy, or imidazole, or, when Z is CH 2 , acylated via coupling with an 20 appropriate R 3

BCH

2

CO

2 H using a standard coupling reagent such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1 hydroxybenzotriazole (HOBT), to provide the final product I'. The 4 chloroquinazolirres-ofi-giuiiblifieslii' -e-either commercially available or can be prepared as outlined in Schemes 6 or 7; the amino cyclic amines are commercially 25 available or are derived from known methods (US4822895; EP401623); and R 3 acylating reagents V' are either commercially available or can be prepared as outlined 78 WO 2006/135636 PCT/US2006/022142 in Scheme 1. Additionally, compounds of Formula I', wherein Z is NH, can be obtained by treatment of intermediate IX' with an appropriate isocyanate. Scheme 4 PPG PG Q. 4C.. R1 x N)K R 1 x

R?

2 N R? 2 N II' VIII' ZR 3 B Z Ra 3 HQ ) q Z"B R 3 O -Q 0 LG /base N Deprotection R - x V' RI X N0 or ' B R? 2 N 0 OH /Coupling Reagent HN R3 wherein: O Q LG is a leaving group Nq PG is a protecting group R 3 BNCO, base R Q is NH or N(alkyl) RX

R

2 N I' 5 A method for preparing FLT3 inhibitors of Formula I', where Q is a direct bond, Z is NH or N(alkyl), and p, q, B, X, R 1 , R 2 , and R 3 are defined as in Formula I', is outlined by the general synthetic route illustrated in Scheme 5. Treatment of an appropriate 4 chloroquinazoline or quinoline II' with a cyclic aminoester X' in a solvent such as 10 -isopropanol-at- a-temperature-of-50C--to

-

50 C-f

I

6 1

R

o w e - d bTF - y b - sic hydrolysis of the ester functionality can provide intermediate XI'. Coupling of an appropriate R 3 BZH, wherein Z is NH or N(alkyl), to XI' using a standard coupling reagent such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or carbonyldiimidazole can provide final compound I'. 79 WO 2006/135636 PCT/US2006/022142 Scheme 5 R3 B cl ,- y.N ,, z Rl (Alkyl)O HO Z R 1) H N 1 x HZ B R1 Z" R 3 R, " X R2 : 2) basic hydrolysis N , , Coupling reagent R2):I N R 2 a N) XI' p Chloroquinazoline II' can be prepared by the reaction sequence illustrated in Scheme 5 6. Starting from a corresponding anthranilic acid XII', treatment with a reagent such as formamidine in a solvent such as ethanol can provide quinazolone XIII'. Subsequent treatment of XIII' with a chlorinating agent, such as phosphorous oxytrichloride, or oxalyl chloride in dimethylformamide (DMF) in a solvent such as dichloroethane, can provide the desired chloroquinazoline II'. The anthranilic acids 10 are either commercially available or can be prepared by known methods (WO9728118). Scheme 6 NH R ~ N0 2 H kNH 2 RIC

N

H chlorination R NH2

-

NH

R

2 NH2

R

2 ): Xll' XIII' II' 15 Preparation of an appropriate 4-chloro-3-cyanoquinoline II' can be prepared by the reaction sequence illustrated in Scheme 7. Starting from an aniline XIV', treatment with cyanoester XV' in a solvent such as toluene at a temperature of 100 oC to 150 oC followed by additional heating at a temperature of 200 'C to 250 'C in a solvent such 20 as 1,2-dichlorobenzene can provide the quinolone XVI'. Subsequent treatment of XVI' with a chlorinating agent, such as phosphorous oxytrichloride, or oxalyl chloride in DMF in a solvent such as dichloroethane, can provide the desired 80 WO 2006/135636 PCT/US2006/022142 chloroquinoline II'. The starting anilines are either commercially available or can be prepared by a number of known methods (e.g. Tet Lett 1995, 36, 2411-2414). Scheme 7 EtO 2 C CN O Cl

R

2

NH

2 XV' R2 O* \ N R 2 N 5 XIV 2) 200-250C XVI H I FLT3 inhibitors of Formula I', wherein R 1 is -CC(CH 2 )nRa and n, p, q, B, X, Z, Q, Ra,

R

2 , and R 3 are defined as in Formula I', can be prepared by the sequence outlined in Scheme 8. Treatment of the appropriate 6-iodo heteroaromatic XVII', prepared by a 10 method outlined in Schemes 1-5, with an appropriate alkynyl alcohol in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium dichloride, a copper catalyst such as copper(I) iodide, a base such as diethyl amine and a solvent such as dimethylformamide at a temperature of 25 oC to 150 oC can provide the alkynyl alcohol XVIII'. Conversion of the alcohol XVIII' to an appropriate leaving group 15 known by those skilled in the art such as a mesylate followed by an SN 2 displacement reaction with an appropriate nucleophilic heterocycle, heteroaryl, amine, alcohol, or thiol can provide the final compound I'. If Ra nucleophile is a thiol, further oxidation of the thiol can provide the corresponding sulfoxides and sulfones. If Ra nucleophile is an amino, acylation of the nitrogen with an appropriate acylating or sulfonylating 20 agent can provide the corresponding amides, carbamates, ureas, and sulfonamides. If the desired Ra is COORy or CONRwRx, these can be derived from the corresponding hydroxyl group. Oxidation of the hydroxyl group to the acid followed by ester or amide formation under conditions known in the art can provide examples wherein Ra is COORy or CONRwRx. One could prepare the compounds wherR2 -sCC(CH-)nR, 25 utilizing the same reaction sequence with the appropriate 7-iodoaryl intermediate. 81 WO 2006/135636 PCT/US2006/022142 Scheme 8 Z' R3 Z R 3 O Q POH O~,-Q N n N LG reagent 12 N. ( , HO RX Pd catalyst HO X base 'N. .) Cul XVII' XVIII' Z R3 Z R 3 O <Q" )q RaNCQ.7) )q NL Ra Nuc O Q b n / a n base X R2

R

2 N XIX' I' wherein: LG is a leaving group Nuc is a nucleophile FLT3 inhibitors of Formula I', wherein R 1 is -CHCH(CH 2 )nRa and n, p, q, B, X, Z, Q, Ra, R 2 , and R 3 are defined as in Formula I', can be prepared by the sequence outlined 5 in Scheme 9. Treatment of the appropriate 6-iodo heteroaromatic XVII', prepared by a method outlined in Schemes 1-5, with an appropriate vinylstannane XX' in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium dichloride and a solvent such as dimethylformamide at a temperature of 25 oC to 150 'C can provide the alkenyl alcohol XXI'. Conversion of the alcohol XXI' to an appropriate 10 leaving group known by those skilled in the art such as a mesylate followed by an SN 2 displacement reaction with an appropriate nucleophilic heterocycle, heteroaryl, amine, alcohol, sulfonamide, or thiol can provide the final compound I'. If Ra nucleophile is a thiol, further oxidation of the thiol can provide the corresponding sulfoxides and sulfones. If Ra nucleophile is an amino, acylation of the nitrogen with an appropriate 15 acylating or sulfonylating agent can provide the corresponding amides, carbamates, ureas, and sulfonamides. If the desired Ra is COORy or CONRwRx, these can be derived from the corresponding hydroxyl group. Oxidation of the hydroxyl group to 82 WO 2006/135636 PCT/US2006/022142 the acid followed by ester or amide formation under conditions known in the art can provide examples wherein Ra is COORy or CONRwRx. The corresponding cis olefin isomers of Formula I can be prepared by the same method utilizing the appropriate cis vinyl stannane reagent. Reduction of the olefin moiety under known conditions can 5 provide the saturated compounds where Rlis -CH 2 CH2(CH 2 )nRa. One could prepare the compounds where R 2 is -CHCH(CH 2 )nRa utilizing the same reaction sequence with the appropriate 7-iodo quinazoline or quinoline. Scheme 9 B Z-R3B O .Q Z R 3 N q XX OH OZQw I2 j (alkyl) 3 Sn n ) q LG reagent R Pd catalyst HO .- X base R XVII'"

R

2 N3 XXII Z- R3 Z R3 O-, ,,Q

-

1 ' ' I. Q ,' On Q Ra Nuc O Q LG base Ra X ' ,,N RN3R 2 N3 XXII' wherein LG is a leaving group Nuc is a nucleophile 10 FLT3 inhibitors of Formula I', where R 1 is phenyl or heteroaryl and p, q, B, X, Z, Q,

R

2 , and R 3 are defined as in Formula I', can be prepared as outlined in Scheme 10. Treatment of compound XVII', which can be_prepared as described in Schemes-l5, with an appropriate aryl boronic acid or aryl boronic ester, ArB(OR) 2 wherein R is H 15 or alkyl, in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium dichloride in a solvent such as toluene at a temperature of 50 oC to 200 oC can provide the final compound I'. The boronic 83 WO 2006/135636 PCT/US2006/022142 acids/boronic esters are either commercially available or prepared by known methods (Synthesis 2003, 4, 469-483; Organic letters 2001, 3, 1435-1437). One could prepare the compounds where R 2 is phenyl or heteroaryl utilizing the same reaction sequence with the appropriate 7-iodo quinazoline or quinoline. Scheme 10 Z R3 Z" R3 ) )q ArB(OR) 2 P )q N N R2Pd catalyst Arx XVII'l Ar is aryl or heteroaryl I' 5 R is H or alkyl FLT3 inhibitors of Formula I', wherein R 2 is -Y(CH 2 )nRa, Q is NH, N(alkyl), or O, and n, p, q, B, X, Z, R 1 , and R 3 are defined as in Formula I', can be prepared by the sequence outlined in Scheme 11. Treatment of compound XXIII', which can be 10 prepared as described in Schemes 1 or 4, with a base such as hydroxide ion or potassium t-butoxide in the presence of a suitable Ra(CH 2 )nYH at a temperature of 25 oC to 150 oC in a solvent such as THF can provide the substituted XXIV'. Deprotection of the amine or alcohol protecting group known to those skilled in the art under standard conditions can provide the intermediate XXV'. Acylation of XXV' 15 in the presence of a base such as diisopropylethylamine with an appropriate reagent V', wherein Z is NH or N(alkyl) and LG is an appropriate leaving group, such as be chloride, imidazole, or p-nitrophenoxy, or, when Z is CH 2 , via coupling with an appropriate R 3

BCH

2

CO

2 H using a standard coupling reagent such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1 20 hydroxybenzotriazole (HOBT), can provide the final compound I'. One could prepare the compounds where R 1 is -Y(CH 2 )nRa utilizing the same reaction sequence with-the-appropriate-6=halogenated-gt]fift-d-qinaz-oline or quinoline. 84 WO 2006/135636 PCT/US2006/022142 Scheme 11 PGQ PGQ- ( bq IN# basee Rl ba x H R2In RX Deprotection "X~ Ra(CH 2 )nYHI Hala N) RanN XXIII' XXIV' Hal=CI, F 0 HQ OR RI 'XLG /base R N RI '[X V' Ri . "X Y):: N) or R(iiy Ir:; XXV' Z IR3 wherein 0 0OH /Coupling Reagent LG is a leaving group PG is a protecting group Alternatively FLT3 inhibitors of Formula I', wherein Q is O, NH or N(alkyl), and p, 5 q, B, X, Z, R 1 , R 2 , and R 3 are defined as in Formula I', may be synthesized as outlined by the general synthetic route illustrated in Scheme 12. Treatment of an appropriate N-protected cyclic amine XXVI', where PG is an amino protecting group known to those skilled in the art, with an acylating agent V', wherein LG may be chloride, imidazole, or p-nitrophenoxy, can provide the acylated intermediate XXVII'. 10 Deprotection of the amino protecting group (PG) of XXVII' under standard conditions known in the art, followed by treatment with an appropriate chloroquinazoline or quinoline II' in a solvent such as isopropanol at a temperature of 50 oC to 150 'C, can provide the final product I'. 85 WO 2006/135636 PCT/US2006/022142 Scheme 12 B Z R3 Z B Ra7 O)Q HQbO LGa Rs O3L QN 1) Deprotection R2 N NqN 2) CIi PG base PG N RxR2r)R:) N XXVII XXVIII R I t wherein I, LG is a leaving group PG is Protecting Group Alternatively FLT3 inhibitors of Formula I', wherein Q is a direct bond, Z is NH or N(alkyl), and p, q, B, X, R 1 , R 2 , and R 3 are defined as in Formula I', may be 5 synthesized as outlined by the general synthetic route illustrated in Scheme 13. Coupling of an appropriate N-protected cyclic amino acid XXVIII', where PG is an amino protecting group known to those skilled in the art, with an appropriate R 3 BZH, wherein Z is NH or N(alkyl), using a standard coupling reagent such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or 10 carbonyldiimidazole, can provide the acylated intermediate XXIX'. Deprotection of the amino protecting group (PG) of XXIX' under standard conditions known in the art, followed by treatment with an appropriate chloroquinazoline or quinoline II' in a solvent such as isopropanol at a temperature of 50 oC to 150 oC, can provide the final product I'. 15 Scheme 13

R

3 BZ HO B OIN O )q HOHZ R r 1) Deprotection N )q )q ,, R )'6p 1 N) x PG Coupling Reagent PG 2) X N PG 2 Cl IHlii r ~ XXVIwl XXIX- R-X - N wherein PG is Protecting Group R 2 N III REPRESENTATIVE FLT3 INHIBITORS OF FORMULA I' 86 WO 2006/135636 PCT/US2006/022142 Representative FLT3 inhibitors of Formula I' synthesized by the afore-mentioned methods are presented hereafter. Examples of the synthesis of specific compounds are presented thereafter. Preferred compounds are numbers 5, 12, 14, 17, 64, 66, 70, 5 71, 74 and 75; particularly preferred are numbers 66, 70, 71, 74 and 75. Compound N-O 1H H N MeO MeO N, H 2 N~O 2 0 1- N MeO N MeO N O N~O 3 H N__ 8 MeO7 87 WO 2006/135636 PCT/US2006/022142 Compound 0 4 NO H N MeON MeO): N 0 N MeO N H 6 ~ N 7 NN MeO MeON H H AN N eO N MeON 88 WO 2006/135636 PCT/US2006/022142 Compound H H 8 N MeO N MeO) N H N INO MeO "N MeO 'N' N N<O 10 H@ 11 N MeO- N MeO N MeO89N 89 WO 2006/135636 PCT/US2006/022142 Compound L117\/\ NH 12 0 N MeO MeO N' H N0 MeO MeO N H 14 0 N HON N) H 0 1 1590 0 N MeO N MeO N 90 WO 2006/135636 PCT/US2006/022142 Compound H H 16 N N - N N 17 0 N S N. N H H N N 18 N MeO . N MeON H I N 91 hO N MeO1N 91 WO 2006/135636 PCT/US2006/022142 Compound NH 20 0 N N 21 N MeO N N 0 22 N MeO N H MeO2N N H 23 MeO~ N MeO&N 92 WO 2006/135636 PCT/US2006/022142 Compound H N~O Nr 'I 24 0 O N H H 25 0O~ N M eO -N MeO C( H H N N 26N MeO CN MeO) N H H 27 N N 93 - N 93 WO 2006/135636 PCT/US2006/022142 Compound H H N N N 28 / N MeO N MeO N H H 29 N N 290 0 N MeO CN MeO0 N H O NO 30 N MeO MeO N H 31 N 0 N MeO 9 MeO) N 94 WO 2006/135636 PCT/US2006/022142 Compound H 32 O N MeO CN MeO N H 33 N 0- N MeO N MeO N H -. 0 35 0O N 5NH 35 0 N MeO N MeO N 95 WO 2006/135636 PCT/US2006/022142 Compound H I O N N H 3N O MeO CN MeO N H H 38 O - 0 H 390 N 96 WO 2006/135636 PCT/US2006/022142 Compound 0 ONO H 40 N MeO CN MeO N 0 N O 42 H 41 N N 0 MeO NO 42 H N MeO O N H H Ne N 43 N N O MeO / N MeO N 97 WO 2006/135636 PCT/US2006/022142 Compound H H 0 44 0 N N MeO ' MeO N H H N N 45 0 N N MeO N MeD "" N H H N N 46 N N~ N Me4 N ON NN MeON H H 47 NN Me98 MeO) N N 98 WO 2006/135636 PCT/US2006/022142 Compound H H N YN 48 0 48 C N MeO . N MeO N H H N YN O MeO5N H H 51N N.N 99N MeO N N MeO &N H H 51 0N ~ * MeO N MeO) NeNN 99 WO 2006/135636 PCT/US2006/022142 Compound 52 "N N 52 MeO N A'N MeO ' N H H 53 0 N MeO ~. "N Meo W" N 0 54 0 N MeO N 0~~~0 H N MeO "N MeO N, 100 WO 2006/135636 PCT/US2006/022142 Compound H NOy 0 0 56 MeO N 0~~0 57 N MeO N 00 ICI N'kNH 58 N MeO ~ 0 NN 59 N MeO N MeO&N N 101 WO 2006/135636 PCT/US2006/022142 Compound N NN NH H 60C N MeO MeO) N~y ,- N ),NH 61 N MeO N MeO) N N N l NH 62 N MeO MeON N 63 N -~ N 102 WO 2006/135636 PCT/US2006/022142 Compound 0i NN NH 64 N MeO HH 65 N MeO& Ny NNH H 66 ( MeO . N MeO& N N NH H -67 N *MeO ~ MeO& Ny 103 WO 2006/135636 PCT/US2006/022142 Compound N~ ;1 NH 68 H N MeO N MeO& N H H N N 69 N FN N O H H N Y-N.N 71 00N 0 71 FO O N 104 WO 2006/135636 PCT/US2006/022142 Compound 0 N NH NH 72 H F N NNH 73 H N N NNH 74 H N 0 N 0 N N ~NH H _ 75 NN 105 WO 2006/135636 PCT/US2006/022142 EXAMPLE 1 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl 5 ester (Compound No. 1) HN\ N MeON MeO N To a vial was placed 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (29 mg, 0.1 mmol), as prepared in Example 3a, 4-isopropylphenyl isocyanate (20 mg, 0.12 mmol) 10 and dichloroethane (1 mL). After the mixture was stirred at 60 'C for 16 hours. the content was subjected to aqueous workup and TLC purification to give the desired product in 65% yield. 1H NMR (300 MHz, CDC1 3 ) 5 8.67 (s, 1H), 7.33-7.25 (m, 3H), 7.18 (d, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.64 (s, 1H), 5.08 (m, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.95-3.89 (m, 2H), 3.55-3.48 (m, 2H), 2.88 (sept, J =6.1 Hz, 1H), 2.22-2.14 (m, 15 2H), 2.04 -1.91 (m, 2H), 1.23 (d, J =6.1 Hz, 6H); LC/MS (ESI): calcd mass 450.2, found 451.6 (M+H) +. EXAMPLE 2 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3 20 yl ester (Compound No. 2) JO-- *p N 0 N 106 WO 2006/135636 PCT/US2006/022142 a. (4-Isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester 0 2 N 5 To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added 4-nitrophenyl chloroformate (4.09 g, 20.3 mmol) portionwise with stirring over ~30 sec with brief ice-bath cooling. After stirring at RT for 1 h, the homogeneous solution was diluted with DCM (100 mL) and washed with 0.6 M HC1 (1 x 250 mL), 0.025 M HC1 (1 x 400 mL), water (1 x 100 mL), and 1 M NaHCO 3 (1 10 x100 mL). The organic layer was dried (Na 2

SO

4 ) and concentrated to give the title compound as a light peach-colored solid (5.80 g, 95%). 1 H NMR (300 MHz, CDC1 3 ) 5 8.28 (m, 2H), 7.42-7.32 (m, 4H), 7.23 (m, 2H), 6.93 (br s, 1H), 2.90 (h, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H). LC/MS (ESI): calcd mass 300.1, found 601.3 (2MH) +. 15 b. (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) pyrrolidin-3-yl ester HN &<

'

0 -id N o N To a mixture of racemic 3-pyrrolidinol (141 mg, 1.62 mmol), 4-chloro-6,7 20 dimethoxyquinazoline (Oakwood Products, Inc) (372 mg, 1.65 mmol), and DIEA (300-L.82Tilml) Wi d a-ddDMSO(l0iL),dii thriiiiture was stirred for 20 min at 100 oC. After cooling to rt, (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (646 mg, 2.15 mmol), prepared as described in the previous step, was added and the crude reaction stirred at 100 oC for 1 min to dissolve the material. The reaction 25 was then cooled on an ice bath, NaH (57 mg, 2.4 mmol) was added in one portion, 107 WO 2006/135636 PCT/US2006/022142 and the reaction mixture was stirred 1-2 min on the ice bath until the bulk of H 2 evolution ceased, after which point the reaction was stirred for 20 min at 80 'C. After cooling to rt, the solution was shaken with 2M K 2

CO

3 (9 mL) and extracted with DCM (2 x 10 mL). The organic layers were combined, dried (Na 2

SO

4 ), and 5 concentrated to give, after purification with flash chromatography (1:2 --> 1:4 hexanes/acetone), the title compound (446 mg, 62%). This material was recrystallized from hot CH 3 CN (30 mL) to provide the title compound as off-white rosettes (363 mg, 50%). 'H NMR (300 MHz, CDCl 3 ) 8 8.52 (s, 1H), 7.38 (s, 1H), 7.29 (m, 2H), 7.21 (s, 1H), 7.16 (m, 2H), 6.87 (br s, 1H), 5.52 (m, 1H), 4.25-3.98 (m, 10 4H), 4.00 (s, 3H), 3.97 (s, 3H), 2.86 (heptet, J = 6.9 Hz, 1H), 2.42-2.17 (m, 2H), 1.22 (d, J = 6.9 Hz, 6H). LC/MS (ESI): calcd mass 436.2, found 437.3 (MH)

+

. Anal. Calcd for C 24

H

28

N

4 0 4 : C, 66.04; H, 6.47; N, 12.84. Found: C, 65.84; H, 6.34; N, 12.86. 15 EXAMPLE 3 (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4 yl ester (Compound No. 3) ON O H N 20 a. 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-ol (N N 1OH 108 WO 2006/135636 PCT/US2006/022142 A solution of 4-hydroxypiperidine (40.4 mg, 0.400 mmol) in isopropanol (1 mL) was treated with 4-chloro-6,7-dimethoxy-quinazoline (89.9 mg, 0.401 mmol). After stirring at 100 oC overnight, the reaction was cooled to RT, partitioned between DCM 5 (10 mL) and H 2 0 (10 mL). The organic phase was dried over Na 2

SO

4 and concentrated in vacuo to afford the title compound as a solid (60 mg, 52%). b. (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) piperidin-4-yl ester 10 O0 O H N To a vial was placed 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (29 mg, 0.1 mmol), essentially as prepared in Example 3a, p-nitrophenyl chloroformate (24 mg, 15 0.12 mmol), triethylamine (20 mg, 0.2 mmol) and dichloroethane (1 mL). After the mixture was stirred at 60 oC for 16 hours, 4-isopropoxyaniline (18 mg, 0.12 mmol) was added. The content was stirred at 60 oC for 12 hours and subjected to aqueous workup and TLC purification to give the desired product in 45% yield. 1H NMR (300 MHz, CDCl 3 ) 8 8.67 (s, 1H), 7.31-7.24 (m, 3H), 7.09 (s, 1H), 6.85 (m, 2H), 6.65 (br 20 s, 1H), 5.07 (m, 1H), 4.48 (sept, J =6.1 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.94-3.88 (m, 2H), 3.54-3.46 (m, 2H), 2.21-2.14 (m, 2H), 1.99-1.91 (m, 2H), 1.31 (d, J =6.1 Hz, 6H); LC/MS (ESI): calcd mass 466.2, found 467.6 (M+H) +. EXAMPLE 4 25 (4-Isopropyl-phenyl)-carbamic acid 1-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin 3-ylmethyl ester (Compound No. 4) 109 WO 2006/135636 PCT/US2006/022142 0 ON H N N Prepared as described in Example 34 except that racemic piperidin-3-methanol and 4 chloro-6,7-dimethoxyquinazoline were used in place of racemic 3-pyrrolidinol and 4 5 chloroquinoline respectively. Also, 4-isopropylphenylisocyanate was used in place of (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester, NaHMDS was omitted, dioxane used in place of THF and the mixture was stirred at 100 oC for 3 h. Purification by flash column chromatography (silica gel; 1-2 % Methanol (MeOH)/DCM) yielded 17.1 mg ( 35 %) of pure (4-isopropyl-phenyl)-carbamic acid 10 1-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-3-ylmethyl ester. 1H NMR (300 MHz, CDC1 3 ): 5 8.66 (s, 1H), 7.31-7.24 (m, 3H), 7.19-7.09 (m, 3H), 6.71 (bs, 1H), 4.29 4.18 (m, 2H), 4.15-3.92 (m, 8H), 3.17-3.04(m, 1H), 2.98-2.82 (m, 2H), 2.27 (m, 1H), 2.18-1.78 (m, 4H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 464.2, found 465.3

(MH)

+

. 15 EXAMPLE 5 2-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-N-(4-isopropyl-phenyl) acetamide (Compound No. 5) 0 N

-

H N 0O) N ) 20 To a solution of 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (73 mg, 0.3 mmol) in anhydrous DCM was added PS-carbodiimide (0.4 mmol) and the mixture was shaken at RT for 15 min. Then, 4-isopropylaniline (27 mg, 0.2 mmol) 110 WO 2006/135636 PCT/US2006/022142 was added to the mixture and it was shaken overnight at rt. It was then filtered and the resin was washed with DCM twice and the combined filtrate and washings were concentrated in vacuo to yield the crude 4

-[(

4 -isopropyl-phenylcarbamoyl)-methyl] piperidine-l1-carboxylic acid tert-butyl ester (5a) which was used as such for the next 5 step. The crude 5a (0.2 mmol) was dissolved in 2 mL of a 3M HC1/MeOH solution and stirred at RT for 1 h. It was then concentrated in vacuo to obtain the crude N-(4 isopropyl-phenyl)-2-piperidin-4-yl-acetamide (Sb) as the HC1 salt which was used as 10 such for the next step. To a solution of 5b (0.1 mmol) in anhydrous isopropanol, was added 4-chloro-6,7 dimethoxyquinazoline (23 mg, 0.1 mmol)followed by DIEA (35 gL, 0.2 mmol) and the mixture was stirred at 100 oC overnight. It was then cooled to RT and 15 concentrated in vacuo. The crude product was purified by Preparative TLC (silica gel, 5 % MeOHIDCM) to yield 16.4 mg (37 %) of pure 2-[1-(6,7-dimethoxy-quinazolin-4 yl)-piperidin-4-yl]-N-(4-isopropyl-phenyl)-acetamide. 1H NMR (300 MHz, CDC1 3 ): 5 8.63 (s, 1H), 7.45 (d, 2H), 7.35 (s, 1H), 7.25 (s, 1H), 7.18 (d, 2H), 7.07 (s, 1H), 4.22 (d, 2H), 3.99 (d, 6H), 3.13 (m, 2H), 2.88 (m, 1H), 2.40-2.22 (m, 3H), 2.04-1.82 (m, 20 2H), 1.62-1.45 (m, 2H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 448.3, found 449.3 (MH) . EXAMPLE 6 2-[11-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-N-(4-isopropyl-phenyl) 25 acetamide (Compound No. 6) HN / N 0 N 111 WO 2006/135636 PCT/US2006/022142 Prepared as described in Example 5 except that racemic 3-carboxymethyl-pyrrolidine 1-carboxylic acid tert-butyl ester was used in place of 4-carboxymethyl-piperidine-1 carboxylic acid tert-butyl ester. Purification by flash column chromatography (silica gel; 1-2 % MeOH/DCM) yielded 15.3 mg (35 %) of pure 2-[11-(6,7-dimethoxy 5 quinazolin-4-yl)-pyrrolidin-3-yl]-N-(4-isopropyl-phenyl)-acetamide. 'H NMR (300 MHz, CDC1 3 ): 8 8.44 (s, 1H), 7.84 (s, 1H), 7.43 (m, 3H), 7.17 (m, 3H), 4.15-4.05 (m, 1H), 4.05-3.90 (m, 8H), 3.79-3.69 (m, 1H), 2.95-2.80 (m, 2H), 2.63-2.47 (m, 2H), 2.38-2.25 (m, 1H), 1.87-1.73 (m, 1H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 434.2, found 435.3 (MH) +. 10 EXAMPLE 7 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl-phenyl)-urea (Compound No. 7) 0 HN O HN MeO N 15 MeO : N To a solution of 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-ylamine trifluoroacetic acid salt (30 mg, 0.08 mmol), prepared as described in Example 35b, and triethylamine (20 mg, 0.2 mmol) in DCM (1 mL) was added 4-isopropylphenyl 20 isocyanate (35 mg, 0.21 mmol). The mixture was stirred at RT overnight and subjected to normal workup and prepared TLC purification to give the desired product (21 mg, 62%). 1 H NMR (300 MHz, CDC1 3 ) 8 8.22 (s, 1H), 7.40 (s, 1H), 7.28-7.04 (m, 6H), 6.63 (s, 1H), 4.62 (m, 1H), 4.09-3.90 (m, 10H), 2.88 (m, J = 6.9 Hz, 1H), 2.20 (m, 2H), 1.2 (d, J= 6.9 Hz, 6H). LC/MS (ESI) calcd mass 435.2, found 436.2 (MH) +. 25 EXAMPLE 8 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropoxy-phenyl)-urea (Compound No. 8) 112 WO 2006/135636 PCT/US2006/022142 0 HN MeOw N MeO N Following the procedure for the synthesis of Example 29 using 1-(6,7-dimethoxy quinazolin-4-yl)-pyrrolidin-3-ylamine trifluoroacetic acid salt, as prepared in Example 5 35b. 'H NMR (300 MHz, CDC1 3 ) 8 8.30 (s, 1H), 7.41 (s, 1H), 7.21-7.01 (m, 4H), 6.80 (d, J = 8.9 Hz, 2H), 6.21 (s, 1H), 4.51 (m, 1H), 4.45 (m, J= 6.1 Hz, 1H), 4.15-3.81 (m, 4H), 3.94 (s, 3H), 3.92 (s, 3H), 2.17 (m, 2H), 1.29 (d, J= 6.1 Hz, 6H). LC/MS (ESI) calcd mass 451.2, found 452.2 (MH) . 10 EXAMPLE 9

(

4 -Isopropyl-phenyl)-carbamic acid 1-[1-( 6

,

7 -dimethoxy-quinazolin-4-yl)-pyrrolidin 2-ylmethyl ester (Compound No. 9) H N OYN O N 0 15 Prepared as described in Example 34 except that racemnic piperidin-2-methanol and 4 chloro-6,7-dimethoxyquinazoline were used in place of racemic 3-pyrrolidinol and 4 chloroquinoline respectively. Also, 4 -isopropylphenylisocyanate was used in place of

(

4 -isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester, NaHMDS was omitted, 20 dioxane used in place of THF and the mixture was stirred at 100 'C for 3 h. Purification by flash column chromatography (silica gel; 1-2 % MeOH/DCM) yielded 5.2 mg-(-12-%) -f-pure- (4-iso propyl-phenyl)=carbantic-ncid-[F-(6-7--dif-efhixy quinazolin-4-yl)-pyrrolidin-2-ylmethyl ester. 'H NMR (300 MHz, CDC1 3 ): 8 8.41 (s, 1H), 7.30 (s, 1H), 7.25-7.05 (mn, 6H), 4.95 (m, 1H), 4.39 (d, 2H), 4.08-3.84 (m, 8H), 25 2.88-2.74 (m, 1H), 2.24-1.82 (m, 4H), 1.16 (d, 6H). LC/MS (ESI): calcd mass 450.2, found 451.3 (MH) +. 113 WO 2006/135636 PCT/US2006/022142 EXAMPLE 10 (4-Isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-piperidin-4-yl ester (Compound No. 10) 0 ON H N 5 N Prepared as described in Example 34 except that 4-hydroxypiperidine was used in place of pyrrolidin-3-ol. Purification by Preparative TLC (silica gel; 5 % MeOH/DCM) yielded 8.8 mg (23 %) of pure (4-isopropyl-phenyl)-carbamic acid 1 10 quinolin-4-yl)-piperidin-4-yl ester. 1H NMR (300 MHz, CDC1 3 ): 8 8.73 (d, 1H), 8.08 (d, 1H), 8.00 (d, 1H), 7.67 (m, 1H), 7.50 (m, 1H), 7.33 (d, 2H), 7.19 (d, 2H), 6.86 (d, 1H), 6.74 (m, 1H), 5.11-5.00 (m, 1H), 3.60-3.35 (m, 2H), 3.15 (m, 2H), 2.95-2.82 (m, 1H), 2.30-2.15 (m, 2H), 2.10-1.95 (m, 2H), 1.24 (d, 6H). LC/MS (ESI): calcd mass 389.2, found 390.3 (MH) . 15 EXAMPLE 11 (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) piperidin-4-yl ester (Compound No. 11) O 0 . OkN N H N 20 -O N a. 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-ol 114 WO 2006/135636 PCT/US2006/022142 OH N '_0 N "0 N To a solution of 4 -chloro-6,7-dimethoxy-quinazoline (96.5 mg, 0.43 mmol) in i-PrOH 5 (2 mL) was added 4-hydroxypiperidine (56.5 mg, 0.56 mmol). The mixture was heated at 95 oC with stirring for 2 h, allowed to cool to room temperature. After 14 h, the precipitate was filtered, washed with EtOAc (3 x 1 mL), dried in vacuo to afford the title compound as a white solid (60 mg, 48.2%). 1H NMR (300 MHz, CDC1 3 ) 8 8.65 (s, 1H), 7.28 (s, 1H), 7.10 (s, 1H), 4.06 (m, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.37 10 (m, 2H), 2.10 (m, 2H), 1.70-1.79 (m, 4H). LC/MS (ESI): calcd mass 289.1; found 290.2 (MH+). b. 2 -Cyclobutoxy-5-nitro-pyridine 0 2 N- -OP 15 ON O A mixture of 2-chloro-5-nitropyridine (7.12 g, 45.0 mmol) and cyclobutanol (3.40 g, 47.2 mmol) in THF (30 mL) was vigorously stirred at 0 oC while Nail (1.18 g, 46.7 mmol) was added in three portions over -10-20 s under air (Caution: Extensive gas 20 evolution). Reaction residue was rinsed down with additional THF (5 mL), followed by stirring under positive argon pressure in the ice bath for 1-2 more minutes. The ice bath was then removed and the brown homogeneous solution was stirred at RT for 1 h.- The-reaction-was-concentrated-under-reduced-pressure-at-O-oC,itF-fip im0.75- M EDTA (tetrasodium salt) (150 mL), and extracted with DCM (1 x 100 mL, 1 x 50 25 mL). The combined organic layers were dried (Na 2

SO

4 ), concentrated, taken up in MeOH (2 x 100 mL) and concentrated under reduced pressure at 60 oC to provide the title compound as a thick dark amber oil that crystallized upon standing (7.01 g, 115 WO 2006/135636 PCT/US2006/022142 80%). 'H NMR (300 MHz, CDC1 3 ) 8 9.04 (dd, J = 2.84 and 0.40 Hz, 1H), 8.33 (dd, J = 9.11 and 2.85 Hz, 1H), 6.77 (dd, J= 9.11 and 0.50 Hz, 1H), 5.28 (m, 1H), 2.48 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H). 5 c. 6-Cyclobutoxy-pyridin-3-ylamine

H

2 N x OP N A flask containing 10% w/w Pd/C (485 mg) was gently flushed with argon while 10 slowly adding MeOH (50 mL) along the sides of the flask, followed by the addition in ~5 mL portions of a solution of 2-cyclobutoxy-5-nitro-pyridine (4.85 g, 25 mmol), as prepared in the previous step, in MeOH (30 mL). (Caution: Large scale addition of volatile organics to Pd/C in the presence of air can cause fire.) The flask was then evacuated one time and stirred under H 2 balloon pressure for 2 h at RT. The reaction 15 was then filtered, and the clear amber filtrate was concentrated, taken up in toluene (2 x 50 mL) to remove residual MeOH, and concentrated under reduced pressure to provide the crude title compound as a translucent dark brown oil with a faint toluene smell (4.41 g, "108%" crude yield). H NMR (300 MHz, CDC1 3 ) 8 7.65 (d, J = 3.0 Hz, 1H), 7.04 (dd, J = 8.71 and 2.96 Hz, 1H), 6.55 (d, J = 8.74 Hz, 1H), 5.04 (m, 1H), 20 2.42 (m, 2H), 2.10 (m, 2H), 1.80 (m, 1H), 1.66 (m, 1H). LC-MS (ESI): calcd mass 164.1, found 165.2 (MH ). d. (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester H 0 N . O N O 25 0 2 N0 A mixture of 6-cyclobutoxy-pyridin-3-ylamine (4.41 g, assume 25 mmol), as prepared in the previous step, and CaCO 3 (3.25 g, 32.5 mmol) (10 micron powder) was treated with a homogeneous solution of 4-nitrophenyl chloroformate (5.54 g, 27.5 mmol) in 116 WO 2006/135636 PCT/US2006/022142 toluene (28 mL) in one portion at rt, and was stirred at "rt" (reaction warmed spontaneously) for 2 h. The reaction mixture was then directly loaded onto a flash silica column (95:5 DCM/MeOH -> 9:1 DCM/MeOH) to afford 5.65 g of material, which was further purified by trituration with hot toluene (1 x 200 mL) to provide the 5 title compound (4.45 g, 54%). 1H NMR (400 MHz, CDCl 3 ) 8 8.32-8.25 (m, 2H), 8.12 (d, 1H), 7.81 (m, 1H), 7.42-7.36 (m, 2H), 6.85 (br s, 1H), 6.72 (d, 1H), 5.19-5.10 (m, 1H), 2.50-2.40 (m, 2H), 2.19-2.07 (m, 2H), 1.89-1.79 (m, 1H), 1.75-1.61 (m, 1H). LC-MS (ESI): calcd mass 329.1, found 330.1 (MH ). 10 e. (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4 yl)-piperidin-4-yl ester 0 -s 0 0 N N -_ON To a solution of 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (30.7 mng, 0.11 15 mmol), as prepared in Example 1 la, in anhydrous THIF (2 mL) was added 60% NaHl (10 mg), followed by (6-cyclobutoxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester (35 mg, 0.11 mmol), as prepared in the previous step. The mixture was stirred at 80 oC for 0.5 h, then concentrated. The residue was purified by preparative TLC (5% MeOH/EtOAc) to afford the title compound as beige solid (17.8 mg, 35%). 'H NMR 20 (300 MHz, CD 3 OD) 8 8.49 (s, 1H), 8.14 (s, 1H), 7.79 (d, J= 7.93 Hz, 1H), 7.17 (d, J = 5.78 Hz, 1H), 7.16 (s, 1H), 6.69 (dd, J= 8.91 and 0.64 Hz, 1H), 5.05 (m, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.93 (m, 2H), 3.62 (m, 2H), 2.43 (m, 2H), 2.04-2.22 (m, 4H), 1.64-2.00 (m, 4H). LC/MS _(ES: calcd mass 479.2, found480.2_(MHW) 25 EXAMPLE 12 (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) pyrrolidin-3-yl ester (Compound No. 12) 117 WO 2006/135636 PCT/US2006/022142 H N ON N N a. 1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-ol 5 OH N """N 0 N Prepared as described in Example 11 a using 3-pyrrolidinol. H NMR (300 MHz, DMSO-d 6 ) 8 8.70 (s, 1H), 7.68 (s, 1H), 7.27 (s, 1H), 4.48 (m, 10 1H), 4.10-4.25 (m, 3 H), 3.96 (s, 6H), 3.90 (m, 1H), 2.05 (m, 2H). LC/MS (ESI): calcd mass 274.1, found 275.2 (MH+). b. (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4 yl)-pyrrolidin-3-yl ester 15 H N O N O ""0 N Prepared utilizing the procedure described in Example 1le using 1-(6,7-Dimethoxy quinazolin-4-yl)-pyrrolidin-3-ol. 20 1 H NMR (300 MHz, CD30D) 8 8.31 (s, 1H), 8.12 (m, 1H), 7.76 (m, 1H), 7.57 (s, 1H), 7.11 (s, 1H), 6.67 (d, J = 9.30 Hz, 1H), 5.47 (m, 1H), 5.02 (m, 1H), 4.29 (dd, J = 118 WO 2006/135636 PCT/US2006/022142 12.60 and 3.90 Hz, 1H), 4.04-4.21 (m, 3H), 3.97 (s, 3H), 3.96 (s, 3H), 2.30-2.48 (m, 4H), 2.02-2.12 (m, 2H), 1.82 (m, 1H), 1.67 (m, 1H). LC/MS (ESI): calcd mass 465.2, found 466.2 (MH+). 5 EXAMPLE 13 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic acid (4-isopropyl phenyl)-amide (Compound No. 13) H 0 NY N MeO N MeO)D N 10 a. 1-(6,7-Dimnethoxy-quinazolin-4-yl)-piperidine-4-carboxylic acid

CO

2 H N MeON MeO N 15 To a sealed tube was placed 4-chloro-6,7-dimethoxyquinazoline (0.30 g, 1.34mmol), ethyl isonipecotate (0.236 g, 1.5 mmol) and 2-propanol (5 mL). The mixture was heated at 100 oC for 16 hours. After cooling to RT, the content was poured into water, the water solution was extracted with DCM. The organic layer was dried and concentrated to give the pure product of ester, which, upon saponification, gave the 20 desired-acid-in-90% yield; -H-NMR-(dyDMSO)-8-876-(s,1H),-7.-3-(s 2H),-4.55-4_1 (m, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.65 (m, 2H), 2.76 (m, 1H), 2.05 (m, 2H), 1.80 (m, 2H). 119 WO 2006/135636 PCT/US2006/022142 b. 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic acid (4-isopropyl phenyl)-amide H ON N MeO C N MeO N 5 To the mixture of 1-( 6 ,7-dimethoxyquinazalin-4-yl)-piperidine-4-carboxylic acid (32 mg, 0.1 mmol), as prepared in the previous step, and 4-isopropylaniline (15 mg, 0.11 mmol) in DMF (1 mL) was added EDC (30 mg, 0.15 mmol), HOBT (2 mg) and triethylamine (20 mg, 0.2 mmnol). After stirring at RT for 16 hours, the content was 10 subjected to aqueous workup and TLC purification to give the desired product in 82% yield. 1 H NMR (300 MHz, CDC1 3 ) 8 8.68 (s, 1H), 7.46 (m, 2H), 7.26 (s, 1H), 7.21 (m, 3H), 7.12 (s, 1H), 4.25-4.21 (m, 2H), 4.03 (s, 3H), 4.00 (s, 3H), 3.12 (m, 2H), 2.89 (sept, J = 6.9 Hz, 1H), 2.55 (m, 1H), 2.24-2.12 (m, 4H), 1.31 (d, J =6.9 Hz, 6H); LC/MS (ESI): calcd mass 434.2, found 435.5 (M+H) . 15 EXAMPLE 14 (4-Isopropyl-phenyl)-carbamic acid 1-[6-(3-hydroxy-prop-1-ynyl)-quinazolin-4-yl] pyrrolidin-3-yl ester (Compound No. 14) HN & / 0 HO N -20 A mixture of (4-isopropyl-phenyl)-carbamic acid 1-(6-iodo-quinazolin-4-yl) pyrrolidin-3-yl ester (63 mg, 125 gmol), prepared as described in Example 20, Cul (1.7 mg, 8.9 gmol), trans-PdC1 2

[P(C

6 Hs) 3

]

2 (3.0 mg, 4.3 pmol), propargyl alcohol (19.2 gL, 325 gmol), and diethylamine (800 gL) was flushed with a stream of argon 120 WO 2006/135636 PCT/US2006/022142 for -15 s, and then quickly sealed and stirred at RT under argon for 2 h. The resulting translucent light amber solution was concentrated under reduced pressure at rt, and then partitioned with DCM (5 mL) and 0.75 M EDTA (tetrasodium salt). The organic layer was dried (Na 2

SO

4 ), concentrated, and purified by flash chromatography (1:9 5 hexanes/EtOAc). The title compound was obtained as a yellowish solid (40.2 mg, 75%). 1H NMR (400 MHz, CDC1 3 ) 5 8.59 (s, 1H), 8.05 (s, 1H), 7.75 (d, 1H), 7.60 (dd, 1H), 7.30 (m, 2H), 7.20-7.13 (m, 3H), 5.51 (m, 1H), 4.53 (s, 2H), 4.17 (m, 1H), 4.11-3.97 (m, 3H), 2.86 (heptet, 1H), 2.40-2.31 (m, 1H), 2.29-2.17 (m, 1H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 430.2, found 431.2 (MH) +. 10 EXAMPLE 15 (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin 3-yl ester (Compound No. 15) 0 N MeO N 15 Following the procedure for the synthesis of Example 3b using 1-(6,7-dimethoxy quinazolin-4-yl)-pyrrolidin-3-ol, prepared essentially as described in Example 3a using pyrrolidinol. 'H NMR (300 MHz, CDC1 3 ) 8 8.52 (s, 1H), 7.38 (s, 1H), 7.38-7.21 (m, 3H), 6.84-6.81 (m, 3H), 5.51 (br s, 1H), 4.47 (m, J = 6.1 Hz, 1H), 4.25-4.05 (m, 20 4H), 4.00 (s, 3H), 3.97 (s, 3H), 2.39-2.23 (m, 2H), 1.30 (d, J = 6.1 Hz, 6H). LC/MS (ESI) calcd mass 452.2, found 453.5 (MH) +. EXAMPLE 16 1-(4-Isopropyl-phenyl)-3-(1-quinazolin-4-yl-pyrrolidin-3-yl) urea (Compound No. -25---16) 121 WO 2006/135636 PCT/US2006/022142 HN ()/ N N A mixture of 4-chloroquinazoline (30.0 mg, 182 pmol), 3-(tert butoxycarbonylamino)pyrrolidine (32.8 mg, 176 tmol), DIEA (33 gLL, 200 gmol), 5 and DMSO (121 gL) was stirred at 100 oC for 20 min. After cooling to rt, TFA (270 gL, 3.6 mmol) was added to the resulting homogeneous yellow solution, and the solution was stirred at 100 oC for 5 min. After cooling to rt, the reaction was diluted with DCM (2 mL) and washed with 2.5M NaOH (1 x 2 mL). The organic layer was collected and concentrated, dissolved in CH 3 CN (100 gL), and (4-isopropylphenyl) 10 carbamic acid 4-nitrophenyl ester (62.5 mg, 208 pmol), as prepared in Example 2a, was added. The reaction was stirred at 100 oC for 20 min, allowed to cool to rt, shaken with 2M K 2

CO

3 (2 mL), and extracted with DCM (2 x 2 mL). The organic layers were combined, dried (Na 2 SO4), and concentrated, and the residue was purified by silica flash chromatography (3:4 hexanes/acetone -- 3:4 toluene/acetone) to afford 15 the title compound as an off-white powder (26.2 mg, 40%). 1H NMR (300 MHz, CDC1 3 ) 8 8.33 (s, 1H), 7.89 (dd, 1H11), 7.72 (dd, 1H11), 7.62 (m, 1H), 7.36 (br s, 1H), 7.28 (m, 1H), 7.22 (m, 2H), 7.10 (m, 2H11), 6.86 (br d, 1H11), 4.65 (m, 1H), 4.07 (dd, 1H), 3.96-3.80 (m, 3H), 2.83 (heptet, 1H), 2.26-2.16 (m, 2H), 1.19 (d, 6H). LC/MS (ESI): calcd mass 375.2, found 376.3 (MH) . 20 EXAMPLE 17 (4-Isopropyl-phenyl)-3-carbamic acid 1-[6-(3-diethylamino-prop-1-ynyl)-quinazolin 4-yl]-pyrrolidin-3-yl ester (Compound No. 17) 122 WO 2006/135636 PCT/US2006/022142 HN 0 N ,/-N N

N-

Methanesulfonic acid 3- { 4

-[

3 -(4-isopropyl-phenylcarbamoyloxy)-pyrrolidin- l-yl] quinazolin-6-yl }-prop-2-ynyl ester 5 HN 0 N MsO ~ N A solution of ( 4 -isopropyl-phenyl)-carbamic acid 1-[6-(3-hydroxy-prop-1-ynyl) quinazolin-4-yl]-pyrrolidin-3-yl ester (32.2 mg, 74.9 gmol), as prepared in Example 10 14, in DCM (500 RL) and TEA (12.5 gL, 89.9 gmol) was treated with methanesulfonyl chloride (6.4 gL, 82.4 gmol) dropwise over ~ 5 s at RT with stirring. The homogeneous yellow solution was stirred at RT for 35 min, then loaded directly onto a silica flash column for purification (1:9 hexanes/EtOAc) to provide the title compound as an off-white foam (30.9 mg, 81%). 'H NMR (400 MHz, CDC1 3 ) 8 8.63 15 (s, 1H), 8.25 (s, 1H), 7.80 (d, 1H), 7.72 (m, 1H), 7.29-7.24 (m, 2H), 7.19-7.14 (m, 2H), 6.61 (br s, 1H), 5.56-5.52 (m, 1H), 5.12 (s, 2H), 4.28-4.22 (m, 1H), 4.20-4.05 (m, 3H), 3.16 (s, 3H), 2.86 (heptet, 1H), 2.44-2.36 (m, 1H), 2.35-2.23 (m, 1H), 1.27 (d, 6H). LC/MS (ESI): calc mass 508.2, found 509.2 (MH) +. 20 ib (4-IsopT6pyl--plenf-Y3-carb-c acid 1-[6-(3-diethylamino-prop-1-ynyl) quinazolin-4-yl]-pyrrolidin-3-yl ester 123 WO 2006/135636 PCT/US2006/022142 HN d0 N N 1 A solution of methanesulfonic acid 3- { 4

-[

3

-(

4 -isopropyl-phenylcarbamoyloxy) pyrrolidin-1-yl]-quinazolin-6-yl }-prop-2-ynyl ester (30.9 mg, 60.8 gmol), as prepared 5 in the previous step, in CH 3 CN (100 gL) was treated with diethylamine (13.9 gL, 134 gmol) rapidly in one portion with stirring at rt. After 20 min stirring at RT, the opaque yellow reaction slurry was directly applied to a flash chromatography column (3:5 hexanes/acetone) to afford the title compound (3.7 mg, 13%). 'H NMR (400 MHz, CDC1 3 ) 8 8.60 (s, 1H), 8.17 (d, 1H), 7.75 (d, 1H), 7.70 (dd, 1H), 7.30-7.23 (m, 10 2H), 7.16 (m, 2H), 6.61 (br s, 1H), 5.54 (m, 1H), 4.27-4.03 (m, 4H), 3.67 (s, 2H), 2.86 (heptet, 1H), 2.65 (q, 4H), 2.42-2.34 (m, 1H), 2.32-2.21 (m, 1H), 1.22 (d, 6H), 1.14 (t, 6H). LC/MS (ESI): calcd mass 485.3, found 486.3 (MH) . EXAMPLE 18 15 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-ylmethyl]-3-(4-isopropyl-phenyl) urea (Compound No. 18) H H N N N ""0 N 20 a. C-[1 -( 6

,

7 -Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-methylamine 124 WO 2006/135636 PCT/US2006/022142

NH

2 N . N 0 N A solution of tert-butyl N-(4-piperidinylmethyl) carbamate (145 mg, 0.678 mmol) in isopropanol (2 mL) was treated with 4-chloro-6,7-dimethoxy-quinazoline (152 mg, 5 0.679 mmol). After stirring at 100 'C overnight, the reaction was cooled to RT and the resulting precipitate in the organic layer was filtered to obtain a crude solid. To the crude solid, TFA (20 mL) and DCM (20 mL) was added and stirred for 30 min, the solvent was concentrated under reduced pressure to afford the title compound as a solid (102 mg, 50%). 'H NMR (300 MHz, CDC1 3 ) 5 8.66 (s, 1H), 7.23 (s, 1H), 7.10 10 (s, 1H), 4.22 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.07 (m, 2H), 2.72 (m, 2H), 1.96 1.92 (m, 2H), 1.55-1.45 (m, 3H); LC/MS (ESI): calcd mass 302.2, found 303.3 [M+1] +. b. 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-ylmethyl]-3-(4-isopropyl 15 phenyl)-urea H H NNN N A solution of C-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-methylamine (47.9 mg, 0.159 mmol), as prepared in the previous step, in acetonitrile (1 mL) was 20 treated with (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (47.6 mg, 0.159 mmol), as prepared in Example 2a. After stirring at 100 'C for 2 h, the reaction was cooled to RT and solvent was removed in vacuo to obtain a crude solid. Purification by prep TLC (1:9 MeOH/DCM) afforded the title compound as a yellow solid (19.3 125 WO 2006/135636 PCT/US2006/022142 mg, 26%). 'H NMR (300 MHz, CDCl 3 ) 8 8.62 (s, 1H), 7.22-7.12 (m, 6H), 7.04-7.02 (m, 2H), 4.16 (m, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.20 (m, 2H), 3.00 (mn, 2H), 2.84 (m, 1H), 1.85-1.82 (m, 3H), 1.44 (m, 2H), 1.19 (d, 6H); LC/MS (ESI): calcd mass 463.3, found 464.3 [M+1] +. 5 EXAMPLE 19 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl-phenyl)-1 methyl-urea (Compound No. 19) \ 0 N MeO N 10 MeO N a. [1-(6,7-Dimnethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-methyl-amine trifluoroacetic acid salt NHMe N MeO N TFA 15 MeO N To a solution of [1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (200 mg, 0.54 mmol), prepared essentially as described in Example 35a, in DMF (1 mL) was added NaH (90%, 30 mg). After the mixture was stirred at 20 RT for 30 minutes, dimethyl sulfate (101 mg, 0.80 mmol) was added. The content was stirred at RT for two hours and heated to 80 'C for another three hours.Normal workup and silica gel column purification gave the N-Boc protected product (152 mg, 73%), which was treated with 50% TFA/CH 2 C1 2 (5 mL). After stirring at room temperature for 3 h, the solution was evaporated to afford the title compound as a 25 trifluoroacetic acid salt. LC/MS (ESI) free base calcd mass 288.2, found 289.3 (MH) +. 126 WO 2006/135636 PCT/US2006/022142 b. 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl phenyl)- 1-methyl-urea O N.KN N MeO N 5 Meo N Following the procedure for the synthesis of Example 7 using [1-(6,7-dimethoxy quinazolin-4-yl)-pyrrolidin-3-yl]-methylamine trifluoroacetic acid salt, as prepared in the previous step. 1H NMR (300 MHz, CDC13) 8 8.54 (s, 1H), 7.41 (s, 1H), 7.30 10 7.04 (m, 5H), 6.38 (s, 1H), 5.22 (m, 1H), 4.10-3.90 (m, 10H), 3.07 (s, 3H), 2.86 (m, J = 6.9 Hz, 1H), 2.31 (m, 2H), 1.21 (d, J= 6.9 Hz, 6H). LC/MS (ESI) calcd mass 449.2, found 450.2 (MH) . EXAMPLE 20 15 (4-Isopropyl-phenyl)-carbamic acid 1-(6-iodo-quinazolin-4-yl)-pyrrolidin- 3 -yl ester (Compound No. 20) HN C / N . N Prepared essentially as described for Example 2b using 4-chloro-6-iodoquinazoline (WO 2004046101), except 1.2 eq nitrophenyl carbamrnate and 1.2 eq NaiH were used. .20- -Flash chromatography-(1-: 1-hexanes/EtOAc--> -1-3-hexanes/EtOAc) afforded-the-title compound as a light yellow solid (70.7 mg, 6.9%). 1 H NMR (400 MHz, CDC1 3 ) 8 8.62 (s, 1H), 8.43 (d, 1H), 7.93 (dd, 1H), 7.58 (d, 1H), 7.28 (m, 2H), 7.16 (m, 2H), 6.71 (br s, 1H), 5.53 (m, 1H), 4.24-4.00 (m, 4H), 2.87 (heptet, 1H), 2.43-2.35 (m, 1H), 127 WO 2006/135636 PCT/US2006/022142 2.32-2.21 (m, 1H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 502.1, found 503.1 (MH) . EXAMPLE 21 5 N-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]- 2 -(4-isopropyl-phenyl) acetamide (Compound No. 21) 0 HN N N --O& 10 a. [1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester 0 HN O N 'ON 15 To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 oC with stirring. After stirring-for-1- h-, the homogeneous solution was conce6ifrte-Tui-de7e-diic-d pressure and the residue was partitioned between EtOAc and water. The organic layers were 20 combined, dried (over Na 2 SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1 H NMR (300 MHz, CD 3 OD) 8 8.58 (s, 1H), 7.34 (s, 1H), 7.18 128 WO 2006/135636 PCT/US2006/022142 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH). b. 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-ylamnine trifluoroacetic acid 5 salt

NH

2 N N . TFA To a solution of [1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-carbamic acid 10 tert-butyl ester (20 mg, 0.052 mmol), as prepared in the previous step, in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was kept stirring for 3 h, concentrated under reduced pressure to afford the title compound as a off white solid (21 mng, 100%). 1H NMR (300 MHz, CD 3 OD) 8 8.65 (s, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.63 (m, 5H), 2.25 (m, 2H), 1.79 (m, 2H). LC/MS (ESI): free 15 base calcd mass 288.2, found 289.2 (MH ). c. N-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-2-(4-isopropyl-phenyl) acetamide 0 HN N 20 N To a mixture of 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ylamine trifluoroacetic acid salt (21 mg, 0.052 mmol), as prepared in the previous step, and (4-isopropyl 129 WO 2006/135636 PCT/US2006/022142 phenyl)-acetic acid (10.1 mg, 0.052 mmol) in anhydrous THF (2 mL) was added HOBT (10.3 mg, 0.067 mmol), followed by HBTU (25.4 mg, 0.067 mmol) and DIEA (33.3 mg, 0.26 mmol). The suspension was stirred at room temperature for 14 h and concentrated under reduced pressure. The residue was purified by flash column 5 chromatography on silica gel (4% MeOH/EtOAc as eluent) to afford the title compound as a white solid (15.5 mg, 67.1%). 'H NMR (300 MHz, CDC13) 8 8.61 (s, 1H), 7.23 (s, 1H), 7.19 (m, 4H), 7.03 (s, 1H), 5.38 (d, J= 6.69 Hz, 1H), 4.12 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.55 (s, 2H), 3.24 (td, J= 12.65 and 2.30 Hz, 2H), 2.90 (m, 1H), 2.06 (m, 2H), 1.46-1.61 (m, 3H), 1.24 (d, J= 6.92 Hz, 6H). LC/MS (ESI): calcd 10 mass 448.3, found 449.2 (MH+). EXAMPLE 22 (4-Isopropyl-phenyl)-carbamiic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4 ylmethyl ester (Compound No. 22) 15 H N o- N a. 4-(Imidazole- 1-carbonyloxymethyl)-piperidine- 1-carboxylic acid tert-butyl ester 20 -N O NY 0 O -N Boc To a solution of 1,1'-carbonyldiimnidazole (145 mg, 0.894 mmol) in DCM (5 mL) was added 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (192 mg, 0.894 130 WO 2006/135636 PCT/US2006/022142 mmol). After stirring at 0 oC overnight, the solvent was removed in vacuo to obtain a crude solid. Purification by prep TLC (1:1 hexanes/EtOAc) afforded the title compound as a solid (167 mg, 61%). 5 b. (4-Isopropyl-phenyl)-carbamic acid piperidin-4-ylmethyl ester H ON N H To a solution of 4-(imidazole-l1-carbonyloxymethyl)-piperidine-l1-carboxylic acid 10 tert-butyl ester (167 mg, 0.540 mmol), as prepared in the previous step, in DMF (2 mL) was added 4-isopropylaniline (0.75 mL, 5.61 mmol). After stirring at 80 oC for 24 h, another portion of 4-isopropylaniline (0.75 mL, 5.61 mmol) was added and stirred at 80 oC for 22 h. The reaction was cooled to RT and the resulting precipitate was filtered to obtain a crude solid. To the crude solid, TFA (10 mL) and DCM (10 15 mL) was added and stirred for 30 min, solvents were concentrated under reduced pressure to afford the title compound as a solid (70 mg, 47%). 'H NMR (300 MHz, CDC1 3 ) 8 7.30-7.26 (min, 2H), 7.18-7.15 (m, 2H), 4.00 (m, 2H), 3.50 (min, 1H), 3.15 (inm, 2H), 2.90 (min, 1H), 2.66 (min, 2H), 2.02 (min, 2H), 1.76 (m, 3H), 1.24 (s, 3H), 1.21 (s, 3H); LC/MS (ESI): calcd mass 276.2, found 318.2 [M+41+1] +. 20 c. (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4 yl)-piperidin-4-ylmethyl ester H NyN N

N

0 N 25 131 WO 2006/135636 PCT/US2006/022142 A solution of (4-isopropyl-phenyl)-carbamic acid piperidin-4-ylmethyl ester (38.9 mg, 0.141 mmol), as prepared in the previous step, in isopropanol (1 mL) was treated with 4-chloro-6,7-dimethoxy-quinazoline (31.6 mg, 0.141 mmol). After stirring at 100 oC for 5 h, the reaction was cooled to RT and solvent was removed by rotovap to obtain 5 crude solid. Purification by silica gel column (3:7 hexanes/EtOAc) afforded the title compound as a solid (1.5 mg, 2.3%). 1 H NMR (300 MHz, CDCl 3 ) 8 8.65 (s, 1H), 7.32-7.29 (m, 3H), 7.19-7.16 (m, 2H), 7.09 (m, 1H), 6.57 (br s, NH), 4.26 (m, 2H), 4.12 (m, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.12 (m, 2H), 2.88 (m, 1H), 1.98 (m, 2H), 1.58 (m, 3H), 1.24 (s, 3H), 1.22 (s, 3H); LC/MS (ESI): calcd mass 464.2, found 10 465.4 [M+1] +. EXAMPLE 23 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic acid (4-isopropoxy phenyl)-amide (Compound No. 23) 15 H O NO N MeO N MeOi N Following the procedure for the synthesis of Example 13b using 4-isopropoxyaniline. 1H NMR (300 MHz, CDC1 3 ) 6 8.67 (s, 1H), 7.42 (d, J = 9.0 Hz, 2H), 7.35 (s, 1H), 20 7.23 (s, 1H), 7.11 (s, 1H), 6.85 (d, J = 9.0 Hz, 2H), 4.50 (sept, J = 6.1 Hz, 1H), 4.24 4.19 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.10 (m, 2H), 2.57 (m, 1H), 2.20-2.10 (m, 4H), 1.31 (d, J = 6.1 Hz, 6H); LC/MS (ESI): calcd mass 450.2, found 451.5 (M+H) . EXAMPLE 24 25 (4-Isopropyl-phenyl)-carbamic acid 1-quinazolin-4-yl-pyrrolidin-3-yl ester (Compound No. 24) 132 WO 2006/135636 PCT/US2006/022142 HN U0 N N a. 4-chloro-quinazoline C1 5 A mixture of 4-hydroxyquinazoline (2.56 g, 17.5 mmol) and POC1 3 (8.0 mL, 88 mmol) was stirred at 140 oC (oil bath) for 10 min. The homogeneous light amber solution was then allowed to cool to RT before concentrating under reduced pressure at 70 oC. The translucent residue was dissolved in DCM (25 mL), and the 10 homogeneous yellow solution was partitioned with ice and 1 M NaHCO 3 to pH ~6 (paper) (~20 mL aq layer). The organic layer was dried twice (Na 2

SO

4 ), filtered through a 0.22 micron filter, and concentrated under reduced pressure (bath < 40 oC) to provide the title compound as a yellow solid (2.53 g, 88%). 'H NMR (300 MHz, CDC1 3 ) 8 9.07 (s, 1H), 8.30 (ddd, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H). 15 b. (4-Isopropyl-phenyl)-carbamic acid 1-quinazolin-4-yl-pyrrolidin-3-yl ester HN 0 N N Prepared essentially as described for Example 2b using 4-chloroquinazoline, prepared 20 as described in the preceding step, except ~ 1.5 eq NaHl was used for the carbamate forming step, with this second step performed at 100 oC for 20 min. Flash chromatography (6:5 hexanes/acetone) provided the title compound as a translucent 133 WO 2006/135636 PCT/US2006/022142 white film (13.5 mg, 20%). 1 H NMR (300 MHz, CDC1 3 ) 8 8.63 (s, 1H), 8.11 (dd, 1H), 7.86 (dd, 1H), 7.71 (m, 1H), 7.41 (min, 1H), 7.31-7.22 (m, 2H), 7.15 (m, 2H), 6.69 (br s, 1H), 5.52 (m, 1H), 4.29-4.02 (m, 4H), 2.86 (heptet, 1H), 2.42-2.20 (m, 2H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 376.2, found 377.3 (MH) +. 5 EXAMPLE 25 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-azetidin-3-ylmethyl]-3-(4-isopropoxy-phenyl) urea (Compound No. 25) H 01 N y NHJ N 10 Oa N a. C-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-azetidin-3-yl]-methylamine

NH

2 N N j 15 A solution of azetidin-3-ylmethyl-carbamic acid tert-butyl ester (76.2 mg, 0.409 mmol) in isopropanol (1 mL) was treated with 4-chloro-6,7-dimethoxy-quinazoline (89.6 mg, 0.400 mmol). After stirring at 100 oC overnight, the reaction was cooled to RT and the solvent was removed in vacuo to obtain a crude solid. To the crude solid, 20 TFA (10 mL) and DCM (10 mL) was added and stirred for 1 h, the solvent was concentrated under reduced pressure to afford the title compound as a solid (42 mg, 38%). 134 WO 2006/135636 PCT/US2006/022142 b. 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-azetidin-3-ylmethyl]-3-(4 isopropoxy-phenyl)-urea H 0~ N NHJ N N~~N 0 N 5 To a solution of 1,1'-carbonyldiimidazole (20.6 mg, 0.127 mmol) in DCM (1 mL) was added 4-isopropoxyaniline (19.4 mg, 0.128 mmol). After stirring at 0 oC for 2 h, C-[1-(6,7-dimethoxy-quinazolin-4-yl)-azetidin-3-yl]-methylamine (35.2 mg, 0.128 mmol), as prepared in the previous step, was added and stirred at RT overnight. The 10 reaction was then partitioned between DCM (10 mL) and H20 (10 mL). The organic phase was dried over NazSO 4 and concentrated in vacuo. Purification by prep TLC (1:9 MeOH/DCM) afforded the title compound as a brown solid (18.1 mg, 31.6%). 1H NMR (300 MHz, CD 3 OD) 8 8.33 (s, 1H), 7.29 (s, 1H), 7.19-7.15 (min, 2H), 7.09 (s, 1H), 6.80-6.77 (m, 2H), 4.71 (min, 2H), 4.50-4.40 (m, 3H), 3.97 (s, 3H), 3.94 (s, 3H), 15 3.52 (min, 2H), 3.07 (mn, 1H), 1.27 (d, 6H); LC/MS (ESI): calcd mass 451.2, found 452.2 [M+1] . EXAMPLE 26 1-[1-(3-Cyano-6,7-dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl-phenyl) 20 urea (Compound No. 26) N 0 H CN N 135 WO 2006/135636 PCT/US2006/022142 a. 2-Cyano-3-(3,4-dimethoxy-phenylamino)-acrylic acid ethyl ester O 1-1)1 NC ' 0 N 1 O1 H 5 To a solution of 3,4-dimethoxyaniline (153 mg, 1 mmol) in toluene (5 mL) was added ethyl(ethoxymethylene)cyanoacetate (169 mg, 1 mmol). The solution was stirred at 100 'C for 1 h and then was stirred at 125 'C for 15 min. The reaction was then cooled to RT and the resulting precipitate in the organic layer was filtered. The solid was washed with hexanes to provide the title compound as a solid. 1H NMR (300 10 MHz, CDC1 3 ) 8 7.77 (d, 1H), 6.85 (d, 1H), 6.70-6.60 (m, 2H), 4.29 (m, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 1.58 (s, NH), 1.37 (m, 3H); LC/MS (ESI): calcd mass 276.1, found 277.1 [M+I] +. b. 6,7-Dimethoxy-4-oxo- 1,4-dihydro-quinoline-3-carbonitrile 15 0 OO CN " /- , N / H A mixture of 2-cyano-3-(3,4-dimethoxy-phenylamino)-acrylic acid ethyl ester (176 mg, 0.638 mmol), as prepared in the previous step, and 1,2-dichlorobenzene (3 mL) 20 was subjected to microwave irradiation at 250 'C for 1 h. The reaction was then cooled to RT, hexanes were added to the mixture and the resulting precipitate in the organic layer was filtered. The solid was washed with hexanes (2 x 10 mL) and DCM (2 x 10 mL), then was dried under reduced pressure to provide the title compound as a solid-(20.8-mg, 14%). 1H NMR-(300-MHz, DMSO-d 6 )8 8.60 (s, 1H), 7.46 (s, 1H), 25 7.05 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H); LC/MS (ESI): called mass 230.1, found 231.1 [M+1] +. c. 4-Chloro-6,7-dimethoxy-quinoline-3-carbonitrile 136 WO 2006/135636 PCT/US2006/022142 CI ON A mixture of 6,7-dimethoxy-4-oxo-1,4-dihydro-quinoline-3-carbonitrile, as prepared 5 in the previous step, and phosphorus oxychloride was stirred at 150 oC for overnight. The reaction was then cooled to RT and phosphorus oxychloride was removed in vacuo to obtain a crude oil. The oil was partitioned between ethyl ether and ice water, the organic phase was dried over Na 2

SO

4 and concentrated under reduced pressure to afford the title compound as a solid. 4-Chloro-6,7-dimethoxy-quinoline-3-carbonitrile 10 can also be prepared by the method described in J. Med. Chem. 43:3244, 2000. 1 H NMR (300 MHz, DMSO-d 6 ) 8 9.00 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 4.02 (s, 6H); LC/MS (ESI): calcd mass 248.0, found 290.1 [M+41+1] . d. 4-(3-Amino-pyrrolidin-1-yl)-6,7-dimethoxy-quinoline-3-carbonitrile 15

NH

2 N >- O): CN A solution of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile (125 mg, 0.502 mmol), as prepared in the previous step, in isopropanol (1 mL) was treated with pyrrolidin-3 20 yl-carbamic acid tert-butyl ester (93.5 mg, 0.502 mmol). After stirring at 100 oC overnight, the reaction was cooled to RT and solvent was removed by rotovap to obtain a crude solid. Then, TFA (1 mL) was added and stirred for 1 h, TFA was concentrated under reduced pressure and CHC1 3 (1 mL) was added with ice. Aqueous

K

2

CO

3 was added dropwise until pH 10. The organic phase was dried over Na 2

SO

4 25 and concentrated in vacuo to afford the title compound as a solid (110 mg, 74%). 137 WO 2006/135636 PCT/US2006/022142 e. 1-[1-(3-Cyano-6,7-dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl phenyl)-urea H HN-< N\/ 0 0 N IO )aN'CN 5 To a solution of 1,1'-carbonyldiimidazole (27.0 mg, 0.166 mmol) in DCM (1 mL) was added 4-(3-amino-pyrrolidin-1-yl)-6,7-dimethoxy-quinoline-3-carbonitrile (49.6 mg, 0.166 mmol), as prepared in the previous step. After stirring at 0 'C for 30 min, 4-isopropylaniline (22.5 mg, 0.166 mmol) was added and stirred at RT overnight. 10 The reaction was then partitioned between DCM (10 mL) and H 2 0 (10 mL). The organic phase was dried over Na 2

SO

4 and concentrated in vacuo. Purification by prep TLC (1:1 hexanes/EtOAc) afforded the title compound as a light brown solid (13.4 mg, 18%). 1H NMR (300 MHz, CDCl 3 ) 8 8.32 (s, 1H), 7.36-7.03 (m, 6H), 5.99 (m, 1H), 4.62 (m, 1H), 4.32-4.23 (m, 2H), 4.04-3.88 (m, 8H), 2.83 (m, 1H), 2.32 (m, 1H), 15 2.14 (m, 2H), 1.19 (d, 6H); LC/MS (ESI): calcd mass 459.2, found 460.2 [M+1] +. EXAMPLE 27 (4-Isopropyl-phenyl)-3-( 1 -quinolin-4-yl)-pyrrolidin-3-yl-urea (Compound No. 27) HN N 20 To a mixture of racemic pyrrolidin-3-yl-carbamic acid tert-butyl ester (102 mg, 0.55 mmol), 4-chloroquinoline (Sigma-Aldrich, Inc) (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 'C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous 138 WO 2006/135636 PCT/US2006/022142

K

2

CO

3 and DCM. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to obtain 155 mg (100 %) of crude (1-quinolin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (27a) which was used as such for the next step. LC/MS (ESI) : 314 (MH) +. 5 The crude 27a (78 mg, 0.25 mmol) was suspended in 5 mL of 50 % TFA/DCM and stirred at RT for 1 h. The mixture was then concentrated in vacuo and the residue was washed with anhydrous ether and the washings were discarded. This was repeated twice more and the residual solid was dried in vacuo to obtain 97 mg (90 %) of the 10 crude 1-quinolin-4-yl-pyrrolidin-3-ylamine (27b) as a yellow semi-solid which was used as such for the next step. LC/MS (ESI): 214 (MH) +. The crude 27b (22 mg, 0.05 mmol) was dissolved in anhydrous THF and triethylamine (20 mg, 0.2 mmol) was added followed by (4-isopropyl-phenyl) 15 carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a, and the mixture was stirred at 70 oC for 1 h. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K 2

CO

3 and EtOAc. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to obtain the crude product which was 20 purified by flash column chromatography (silica gel; 1-2% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH 3 ) to yield 10 mg (54 %) of pure (4-isopropyl-phenyl)-3-(1 quinolin-4-yl)-pyrrolidin-3-yl-urea. 1H NMR (300 MHz, CDC1 3 ): 8 8.07-7.97 (m, 2H), 7.94-7.84 (m, 2H), 7.62-7.5 (m, 2H11), 7.31-7.23 (m, 3H), 7.11-7.05 (m, 2H), 5.81 (d, 1H), 4.74-4.64 (m, 1H11), 4.09-4.00 (dd, 1H), 3.66-3.38 (m, 3H), 2.88-2.74 (heptet, 25 1H), 2.34-1.90 (m, 2H), 1.18 (d, 6H11). LC/MS (ESI) : calcd mass 374.2, found 375.2

(MH)

+. EXAMPLE 28 1[1-( 6 ,7-Dimethoxy-quinazolin-4-yl)-piperidin-3-yl]-3-(4-isoprpy-phenyl)-urea 30 (Compound No. 28) 139 WO 2006/135636 PCT/US2006/022142 H H N N,:N __ N Prepared as described in Example 27 except that racemic piperidin-3-yl-carbamic acid tert-butyl ester and 4-chloro-6,7-dimethoxyquinazoline were used in place of racemic 5 pyrrolidin-3-yl-carbamic acid tert-butyl ester and 4-chloroquinoline respectively. Also, 4-isopropylphenylisocyanate was used in place of (4-isopropyl-phenyl) carbamic acid 4-nitro-phenyl ester, dioxane used in place of THF and the mixture was stirred at 100 oC for 3 h. Purification by flash column chromatography (silica gel; 2 3% MeOH/DCM) yielded 30 mg (67 %) of pure 1-[1-(6,7-dimethoxy-quinazolin-4 10 yl)-piperidin-3-yl]-3-(4-isopropyl-phenyl)-urea. 1H NMR (300 MHz, CDC1 3 ): 8 8.32 (s, 1H), 7.21 (s, 1H), 7.17 (d, 2H), 7.02 (m, 3H), 4.09 (m, 1H), 4.00-3.78 (m, 9H), 3.60 (m, 1H), 2.79 (m, 1H), 2.12-1.91 (m, 2H), 1.82-1.65 (m, 2H), 1.16 (d, 6H). LC/MS (ESI) : calcd mass 449.2, found 450.4 (MH) +. 15 EXAMPLE 29 1-[1-(3-Cyano-6,7-dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropoxy phenyl)-urea (Compound No. 29) H HN N 0 20 Toasolution of 1,1'-carbonyldiimidazole (29.0 mg, 0.179 mmol) in DCM (1 mL) was added 4-(3-amnino-pyrrolidin-1-yl)-6,7-dimethoxy-quinoline-3-carbonitrile (53.3 mg, 0.179 mmol), as prepared in Example 26d. After stirring at 0 oC for 30 min, 4 isopropoxyaniline (27.0 mg, 0.179 mmol) was added and stirred at RT overnight. The 140 WO 2006/135636 PCT/US2006/022142 reaction was then partitioned between DCM (10 mL) and H20 (10 mL). The organic phase was dried over Na 2

SO

4 and concentrated in vacuo. Purification by prep TLC (1:1 hexanes/EtOAc) afforded the title compound as a light brown solid (13.9 mg, 16%). 'H NMR (300 MHz, CDCl 3 ) 5 8.34 (s, 1H), 7.28-7.24 (m, 1H), 7.15 (d, 2H), 5 6.93 (s, 1H), 6.78 (d, 2H), 5.73 (br s, NH), 4.56 (br s, NH), 4.43 (m, 1H), 4.20 (m, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.84 (m, 2H), 2.30-2.04 (m, 3H), 1.28 (d, 6H); LC/MS (ESI): calcd mass 475.2, found 476.2 [M+1] +. EXAMPLE 30 10 1(- 6

,

7 -Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic acid (3-isopropoxy phenyl)-amide (Compound No. 30) H 0 N O N MeO N MeO N 15 Following the procedure for the synthesis of Example 13b using 3-isopropoxyaniline. 'H NMR (300 MHz, CDC1 3 ) 8 8.68 (s, 1H), 7.39-7.35 (m, 2H), 7.24 (s, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.10 (s, 1H), 6.95 (d, J = 8.6 Hz, 1I), 6.66 (dd, J = 8.1 Hz, 2.3 Hz, 1H), 4.56 (sept, J = 6.1 Hz, 1H), 4.24-4.19 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.10 (m, 2H), 2.57 (m, 1H), 2.23-2.10 (m, 4H), 1.33 (d, J = 6.1 Hz, 6H); LC/MS (ESI): 20 calcd mass 450.2, found 451.5 (M+H) . EXAMPLE 31 (4-Isopropyl-phenyl)-carbamic acid 1-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin 3-yl] ester (CompoundNo. 31) 141 WO 2006/135636 PCT/US2006/022142 H O N N Racemic piperidin-3-ol (15 mg, 0.115 mmol) and 4-chloro-6,7-dimethoxyquinazoline (23 mg, 0.1 mmol) were dissolved in anhydrous dioxane. PS-NMM (Argonaut, Inc) 5 (100 mg, 0.3 mmol) was added and the mixture was stirred at 100 'C for 3h and then cooled to rt. PS-isocyanate (Argonaut, Inc) (100 mg, 0.3 mmol) was then added and the mixture was shaken at RT for 3 h. It was then filtered and the resins were washed with dioxane. To the combined filtrate and washings was added 4 isopropylphenylisocyanate (0.15 mmol) and the mixture was stirred at 100 oC for 3 h 10 and then cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-1 % MeOHIDCM) to obtain 31 mg (70 %) of pure (4-isopropyl-phenyl)-carbamic acid 1-[1-(6,7-dimethoxy-quinazolin-4-yl) piperidin-3-yl] ester. 1H NMR (300 MHz, CDC1 3 + CD 3 OD): 8 8.50 (s, 1H), 7.22 (s, 1H), 7.18-7.00 (m, 5H), 4.98 (m, 1H), 4.14-3.80 (m, 8H), 3.75-3.45 (m, 3H), 2.79 (m, 15 1H), 2.15-1.70 (m, 3H), 1.16 (d, 6H). LC/MS (ESI): calcd mass 450.2, found 451.4

(MH)

. EXAMPLE 32 (4-Isopropoxy-phenyl)-carbamic acid 1-(3-cyano-6,7-dimethoxy-quinolin-4-yl) 20 pyrrolidin-3-yl ester (Compound No. 32) HN O 0 N OO CN a. (4-Isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester 142 WO 2006/135636 PCT/US2006/022142 HN O 0 2 N Prepared essentially as described for Example 2a using 4-isopropoxyaniline, except the water and IM NaHCO 3 washes were omitted. The title compound was obtained as a light violet-white solid (16.64g, 98%). 1H NMR (300 MHz, CDC1 3 ) 8 8.26 (m, 5 2H), 7.40-7.28 (m, 4H), 6.98 (br s, 1H), 6.87 (m, 2H), 4.50 (heptet, J = 6.0 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H). LC/MS (ESI): calcd mass 316.1, found 633.2 (2MH) . b. (4-Isopropoxy-phenyl)-carbamic acid 1-(3-cyano-6,7-dimethoxy-quinolin-4 10 yl)-pyrrolidin-3-yl ester HN O 0 N ON CN Prepared essentially as described for Example 2b, using 4-chloro-6,7-dimethoxy quinoline-3-carbonitrile, prepared as described in Example 26c, and (4-isopropoxy 15 phenyl)-carbamic acid 4-nitro-phenyl ester, as prepared above, except the SNAr reaction was performed at 100 'C for 30 min, and a total of -2-2.5 eq NaH was added in two portions for the carbamate-forming step, with this second step performed at 80 oC for 30 min. Flash chromatography (1:2 hexanes/EtOAc) afforded the title compound (4.6 mg, 8.3%). 'H NMR (300 MHz, CDC1 3 ) 5 8.52 (s, 1H), 7.335 (s, 1H), -20 7.328 (s, 1H), 7.24 (m, 2H), 6.83 (mi, 2H), 6.62 (br s, 1H), 5.49 (m, 1H), 4.48 (heptet, 1H), 4.46-4.31 (m, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 4.02-3.95 (m, 2H), 2.39-2.31 (m, 2H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 476.2, found 477.3 (MH) . EXAMPLE 33 143 WO 2006/135636 PCT/US2006/022142 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-2 ylmethyl ester (Compound No. 33) H N O0 5 Prepared as described in Example 34 except that racemic piperidin-2-methanol and 4 chloro-6,7-dimethoxyquinazoline were used in place of racemic 3-pyrrolidinol and 4 chloroquinoline respectively. Also, 4-isopropylphenylisocyanate was used in place of (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester, NaHMDS was omitted, dioxane used in place of THF and the mixture was stirred at 100 oC for 3 h. 10 Purification by flash column chromatography (silica gel; 1-2 % MeOH/DCM) yielded 3.4 mg (8 %) of pure (4-isopropyl-phenyl)-carbamic acid 1-[1-(6,7 dimethoxy-quinazolin-4-yl)-piperidin-2-ylmethyl ester. 'H NMR (300 MHz, CDC1 3 ): 8 8.68 (s, 1H), 7.62 (s, 1H), 7.32-7.27 (m, 4H), 7.16-7.11 (m, 2H), 4.96-4.89 (m, 1H), 4.74-4.64 (m, 1H), 4.62-4.53 (m, 1H), 4.28 (m, 1H), 4.02 (s, 3 H), 3.74 (s, 3H), 3.00 15 2.82 (m, 2H), 1.98-1.86 (m, 1H), 1.85-1.50 (m, 5H), 1.22 (d, 6H). LC/MS (ESI) : calcd mass 464.2, found 465.3 (MH) . EXAMPLE 34 (4-Isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester (Compound 20 No. 34) HN d0 N N) To a mixture of racemic 3-pyrrolidinol (48 mg, 0.55 mmol) and 4-chloroquinoline (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred 25 overnight at 100 oC. After cooling to rt, it was concentrated in vacuo. The residue 144 WO 2006/135636 PCT/US2006/022142 was partitioned between aqueous K 2

CO

3 and DCM. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to obtain 105 mg (100 %) of crude 1-quinolin-4-yl-pyrrolidin 3-ol (34a) which was used as such for the next step. 5 The crude 34a (11 mg, 0.05 mmol) was dissolved in anhydrous THF and stirred at RT while a 1.0 M solution of NaHMDS in THF (0.1 mL, 0.1 mmol) was added to it followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a. The mixture was stirred at RT for 30 10 min and then at 80 oC for 30 min. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K 2

CO

3 and EtOAc. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by Preparative TLC (silica gel; 5 % MeOH/DCM) to yield 6.9 mg (37 %) of pure (4 15 isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester. 1 H NMR (300 MHz, CDC1 3 ): 5 8.49 (d, 1H11), 8.18 (d, 1H), 8.07 (d, 1H1), 7.63 (m, 1H), 7.39 (m, 1H), 7.31-7.24 (m, 2H11), 7.16 (m, 2H), 6.82 (bs, 1H), 6.48 (d, 1H), 5.53 (m, 1H11), 4.16-4.08 (m, 1H), 4.02-3.90 (m, 1H), 3.86-3.70 (m, 2H1), 2.92-2.80 (m, 1H), 2.40-2.2 (m, 2H11), 1.21 (d, 6H1). LC/MS (ESI): calcd mass 375.2, found 376.2 (MH)

+

. 20 EXAMPLE 35 N-[1-( 6 ,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-2-(4-isopropyl-phenyl) acetamide (Compound No. 35) HN b 0 N 25 'O N a. [1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester 145 WO 2006/135636 PCT/US2006/022142 0 N -_O N To a solution of 4-chloro-6,7-dimethoxy-quinazoline (48.5 mg, 0.22 mmol) in i-PrOH 5 (2 mL) was added 3-(tert-butoxycarbonylamino)pyrrolidine (44.2 mg, 0.24 mmol), followed by DIEA (55.8 mg, 0.43 mmol). The mixture was heated at 100 'C with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na 2 SO4) and concentrated to give the title 10 compound as a white solid (60 mg, 78%). 'H NMR (300 MHz, CDC1 3 ) 8 8.40 (s, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 5.19 (d, J= 6.72 Hz, 1H), 4.10 (m, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.84 (dd, J= 11.35 and 3.70 Hz, 2H), 3.63 (m, 1H), 2.24 (m, 1H), 2.08 (m, 1H), 1.42 (s, 9H). LC/MS (ESI): calcd mass 374.2, found 375.3 (MH ). 15 b. 1-( 6 ,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-ylamnine trifluoroacetic acid salt

NH

2 N JO N . TFA N 20 [1-( 6

,

7 -Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (38 mg, 0.10 mmol), as prepared in the previous step, was treated with 50% TFA/DCM (5 mL). After stirring at room temperature for 3 h, the solution was evaporated to afford the title compound as a semisolid (48 mg, 100%). 'H NMR (300 MHz, CD 3 OD) 8 8.63 (s, 1H), 7.68 (s, 1H), 7.23 (s, 1H), 4.31 (m, 1H), 4.15 (m, 2H), 146 WO 2006/135636 PCT/US2006/022142 4.05 (s, 3H), 4.02 (s, 3H), 3.72 (m, 1H), 3.22 (m, 1H), 2.58 (m, 1H), 2.38 (m, 1H). LC/MS (ESI): free base called mass 274.1, found 275.2 (MH+). c. N-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-2-(4-isopropyl 5 phenyl)-acetamide H N

-

O b N -_ON To a mixture of 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-ylamine 10 trifluoroacetic acid salt (38 mg, 0.10 mmol), as prepared in the previous step, and (4 isopropyl-phenyl)-acetic acid (18 mg, 0.10 mmol) in anhydrous THF (2 mL) was added HOBT (20 mg, 0.13 mmol), followed by HBTU (49.3 mg, 0.13 mmol) and DIEA (64.6 mg, 0.50 mmol). The suspension was stirred at room temperature for 14 h and concentrated under reduced pressure. The residue was purified by flash column 15 chromatography on silica gel (5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (40 mg, 92%). 'H NMR (300 MHz, CDC1 3 ) 8 8.32 (s, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.18 (s, 4H), 6.28 (br, 1H), 4.65 (m, 1H), 4.09 (m, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.82 (m, 2H), 3.57 (s, 2H), 2.88 (m, 1H), 2.29 (m, 1H), 2.02 (m, 1H), 1.2 (d, J = 6.92 Hz, 6H). LC/MS (ESI): calcd mass 434.2, found 435.3 20 (MH ). EXAMPLE 36 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropoxy-phenyl)-1 methyl-urea (Compound No. 36) 25 147 WO 2006/135636 PCT/US2006/022142 \ 0 MeO N MeO ,N Following the procedure for the synthesis of Example 29 using 1-(6,7-dimethoxy quinazolin-4-yl)-pyrrolidin-3-yl-methylamine trifluoroacetic acid salt, prepared as 5 described in Example 19a. 'H NMR (300 MHz, CDC13) 5 8.52 (s, 1H), 7.42 (s, 1H), 7.27-7.24 (m, 3H), 6.84 (d, J = 8.9 Hz, 2H), 6.29 (s, 1H), 5.22 (m, 1H), 4.48 (m, J = 6.0 Hz, 1H), 4.15-3.81 (m, 4H), 4.01 (s, 3H), 3.97 (s, 3H), 3.01 (s, 3H), 2.24 (m, 2H), 1.30 (d, J = 6.0 Hz, 6H). LC/MS (ESI) calcd mass 465.2, found 466.2 (MH) +. 10 EXAMPLE 37 (4-Isopropyl-phenyl)-carbamic acid 1-(3-cyano-6,7-dimethoxy-quinolin-4-yl) pyrrolidin-3-yl ester (Compound No. 37) HN (:

/

N O CN 15 Prepared essentially as described for Example 2b, using 4-chloro-6,7-dimethoxy quinoline-3-carbonitrile, as prepared in Example 26c, except the SNAr reaction was performed at 100 oC for 30 min, and a total of ~2-2.5 eq NaIH was added in two portions for the carbamate-forming step, with this second step performed at 80 oC for 30 min. Flash chromatography (1:3 hexanes/EtOAc) afforded the title compound (2.2 20 mg, 3.8%). HNMR (300 MHz, CDC1 3 ) 8-8.52 (s,-1H), 7.35-(s,-1H); 7.33-(s, 1H), 7.27 (m, 2H), 7.16 (m, 2H), 6.65 (br s, 1H), 5.50 (m, 1H), 4.47-4.32 (m, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 4.03-3.97 (m, 2H), 2.87 (heptet, 1H), 2.40-2.32 (m, 2H), 1.22 (d, 6H). LC/MS (ESI): caled mass 460.2, found 461.3 (MH) +. 148 WO 2006/135636 PCT/US2006/022142 EXAMPLE 38 (4-Isopropoxy-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea (Compound No. 38) HN0 O N N 5 Prepared as described in Example 27 except that (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester, prepared as described in Example 32a, was used in place of (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester. Purification by flash column chromatography (silica gel; 1-2% MeOH/DCM followed by 90:9:1 10 DCM:MeOH:NH 3 ) yielded 10.4 mg (53 %) of pure (4-isopropoxy-phenyl)-3-(1 quinolin-4-yl)-pyrrolidin-3-yl-urea. 'H NMR (300 MHz, CDC1 3 ): 8 8.01 (dd, 1H11), 7.96 (d, 1H), 7.88 (dd, 1H1), 7.79 (bs, 1H), 7.58-7.52 (m, 1H), 7.35 (br m, 1H), 7.27 (m, 1H), 7.23 (m, 2H), 6.81-6.74 (m, 2H), 5.85 (d, 1H), 4.67 (m, 1H), 4.47-4.37 (m, 1H), 4.08-4.00 (m, 1H1), 3.67-3.4 (m, 3H), 2.3-2.1 (m, 2H), 1.28 (d, 6H). LC/MS 15 (ESI) : calcd mass 390.2, found 391.2 (MH) . EXAMPLE 39 (4-Isopropoxy-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester (Compound No. 39) HN .

0 00 O O N Prepared as described in Example 34 except that (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester, prepared as described in Example 32a, was used in place of (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester. Purification by Preparative TLC (silica gel; 5 % MeOH/DCM) yielded 5.7 mg (30 %) of pure (4-isopropoxy 149 WO 2006/135636 PCT/US2006/022142 phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester. 1H NMR (300 MHz, CDC1 3 ): 5 8.71 (s, 1H), 8.46 (d, 1H), 8.21 (d, 1H), 7.73-7.64 (m, 1H), 7.48-7.39 (m, 1H), 7.22 (m, 2H), 6.83 (d, 2H), 6.75-6.62 (mn, 1H), 6.5 (d, 1H), 5.54 (m, 1H), 4.52 4.42 (m, 1H), 4.24-4.12 (m, 1H), 4.08-3.94 (m, 1H), 3.94-3.74 (mn, 2H), 2.50-2.18 (m, 5 2H), 1.30 (d, 6H). LC/MS (ESI) : calcd mass 391.2, found 392.2 (MH) +. EXAMPLE 40

(

4 -Isopropoxy-phenyl)-carbamic acid 1-(3-cyano-6,7-dimethoxy-quinolin-4-yl) piperidin-4-yl ester (Compound No. 40) 0 HN O N MeO CN 10 MeO N Prepared essentially as described for Example 34, using 4-chloro-6,7-dimethoxy quinoline-3-carbonitrile (J. Med. Chem. 43:3244, 2000), (4-isopropoxy-phenyl) carbamic acid 4-nitro-phenyl ester, as prepared in Example 32a, and 4 15 hydroxypiperidine (Acros, less than 1% water, K.F.), except -1.5 eq NaH used. Flash chromatography (1:2 hexanes/EtOAc) afforded the title compound as a yellow film (11.4 mg, 10.5%). 'H NMR (300 MHz, CDC1 3 ) 8 8.63 (s, 1H), 7.40 (s, 1H), 7.30 (m, 2H), 7.21 (s, 1H), 6.86 (m, 2H), 6.56 (br s, 1H), 5.14 (m, 1H), 4.49 (heptet, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.87-3.74 (m, 2H), 3.63-3.52 (m, 2H), 2.30-2.18 (m, 2H), 2.11 20 1.96 (m, 2H), 1.33 (d, 6H). LC/MS (ESI): calcd mass 490.2, found 491.3 (MH) +. EXAMPLE 41 (4-Isopropoxy-phenyl)-carbamic acid 1-quinolin-4-yl)-piperidin-4-yl ester (Compound No. 41) 150 WO 2006/135636 PCT/US2006/022142 0 0 ON H N )N) Prepared as described in Example 39 except that 4-hydroxypiperidine was used in place of pyrrolidin-3-ol. Purification by Preparative TLC (silica gel; 5 % 5 MeOH/DCM) yielded 1 mg (5 %) of pure (4-isopropoxy-phenyl)-carbamic acid 1 quinolin-4-yl)-piperidin-4-yl ester. 'H NMR (300 MHz, CDCl 3 ): 5 8.75-8.63 (m, 1H), 8.13-7.86 (m, 3H), 7.76-7.60 (m, 2H), 6.92-6.84 (d, 2H), 6.54 (m, 2H), 5.25-5.12 (m, 1H), 4.55-4.45 (m, 1H), 4.2-3.6 (m, 4H), 2.35-2.00 (m, 4H), 1.32 (d, 6H). LC/MS (ESI) : calcd mass 405.2, found 406.2 (MH) . 10 EXAMPLE 42 (4-Isopropyl-phenyl)-carbamniic acid 1-(3-cyano-6,7-dimethoxy-quinolin-4-yl) piperidin-4-yl ester (Compound No. 42) HN OkO N 15 CN 15 O) N, a. (4-Isopropyl-phenyl)-carbamic acid piperidin-4-yl ester 151 WO 2006/135636 PCT/US2006/022142 HN N H To a solution of 1,1'-carbonyldiimidazole (304 mg, 1.88 mmol) in DCM (10 mL) was added 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (350 mg, 1.74 mmol). 5 After stirring at 0 'C for 30 min, 4-isopropylaniline (251 mg, 1.86 mmol) was added and stirred at RT. After stirring overnight, the solvent was removed in vacuo to obtain a crude solid. To the crude solid, TFA (20 mL) and DCM (20 mL) was added and stirred for 30 min, the solvent was concentrated under reduced pressure to afford the title compound as a solid (113 mg, 25%). 'H NMR (300 MHz, CDC1 3 ) 8 7.31 (m, 10 2H), 7.14 (m, 2H), 4.82 (br s, NH), 3.07 (m, 3H), 2.89-2.74 (m, 3H), 1.92 (m, 2H), 1.61 (m, 2H), 1.22 (s, 3H), 1.19 (s, 3H); LC/MS (ESI): calcd mass 262.2, found 263.2 [M+1] +. b. (4-Isopropyl-phenyl)-carbamic acid 1-(3-cyano-6,7-dimethoxy-quinolin-4-yl) 15 piperidin-4-yl ester HN N O CN - N A solution of (4-isopropyl-phenyl)-carbamnic acid piperidin-4-yl ester (44 mg, 0.168 20 mmol), as prepared in the previous step, in isopropanol (1 mL) was treated with 4 152 WO 2006/135636 PCT/US2006/022142 chloro-6,7-dimethoxy-quinoline-3-carbonitrile (42 mg, 0.169 mmol), as prepared in Example 26c. After stirring at 100 oC overnight, the reaction was cooled to RT, partitioned between DCM (10 mL) and H 2 0 (10 mL). The organic phase was dried over Na 2

SO

4 and concentrated in vacuo. Purification by prep TLC (1:1 5 hexanes/EtOAc) afforded the title compound as a light yellow solid (4.7 mg, 5.9%). 1H NMR (300 MHz, CDCl 3 ) 5 8.63 (s, 1H), 7.38-7.18 (min, 6H), 6.69 (br s, NH), 5.14 (m, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.80 (m, 2H), 3.58 (m, 2H), 2.90 (min, 1H), 2.25 (inm, 2H), 2.06 (m, 2H), 1.23 (d, 6H); LC/MS (ESI): calcd mass 474.2, found 475.3 [M+1] +. 10 EXAMPLE 43 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-morpholin-4-yl-phenyl) urea (Compound No. 43) H H N -f N N N N O MeO N 15 MeO N a. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester; hydrochloride H 0 N HCI OgN 0 2 N 00 20 A solution of 4-nitrophenyl chloroformate (798 mg, 3.96 mmol) in THF (2.0 mL) was added rapidly by syringe over ~-10 s at rt under air to a stirred solution of 4 -morpholin-4-yl--ph-enylamnine (675 mg, 3.79 mmol) in THF (8.8 mL), with a heavy grey precipitate forming "instantly". The reaction was immediately capped and stirred "rt" for 30 min (vial spontaneously warmed), and was then filtered. The grey 25 filter cake was washed with dry THF (2 x 10 mL), and dried under high vacuum at 80 'C to afford the title compound as a grey powder (1.361 g, 95%). A portion was 153 WO 2006/135636 PCT/US2006/022142 partitioned with CDCl 3 and aqueous 0.5 M trisodium citrate to generate the CDC1 3 soluble free base: 'H-NMR (300 MHz, CDCl 3 ) 8 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.88 (m, 3H), 3.87 (m, 4H), 3.14 (m, 4H). 5 b. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester H ONN 0 0 2 N TEA (3.033 g, 30.0 mmol) was added rapidly as a stream over 1-2 min to a stirred mixture of (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (10.81 g, 28.48 mmol) (Example 43a) in water (100 mL) at rt. The 10 slurry was stirred for 5 min and then filtered. The olive drab filter cake was stirred in rt water (50 mL) for 5 min and then filtered to remove residual TEA-HC1. The filter cake was then stirred with and filtered from ether twice (1 x 50 mL, 1 x 30 mL). The filter cake was then partially dissolved in boiling EtOAc (100 mL), and the cloudy "solution" filtered hot through a pad of celite. The resulting clear yellow filtrate was 15 allowed to cool to rt, at which point the title compound crystallized out of solution as the free base. The crystals were filtered, washed (1 x 30 mL ether), and allowed to air dry to afford the title compound as yellow needles (5.36 g, 50%). 1 H-NMR (300 MHz, CDC1 3 ) 8 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.88 (m, 3H), 3.87 (m, 4H), 3.14 (m, 4H). 20 c. 1-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-morpholin-4-yl phenyl)-urea H H NN N 0_, Meo ~ N MeO): N) 25 Prepared essentially as described in Example 50b using (4-morpholin-4-yl-phenyl) carbamic acid 4-nitro-phenyl ester (Example 43b). 'H NMR (400 MHz, CDC1 3 ) 8 154 WO 2006/135636 PCT/US2006/022142 8.37 (s, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 7.16 (m, 2H), 6.85 (m, 2H), 6.60 (br s, 1H), 5.60 (br s, 1H), 4.61 (m, 1H), 4.10 (dd, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.93 (m, 2H), 3.88-3.80 (m, 5H), 3.11 (m, 4H), 2.28 (m, 1H), 2.11 (m, 1H). LC/MS (ESI): calcd mass 478.2, found 479.1 (MH) +. 5 EXAMPLE 44 1-(6-Cyclobutoxy-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazoin-4-y)-pyrrolidin-3 yl]-urea (Compound No. 44) H H O N N MeO N 10 MeO N: Prepared essentially as described in Example 50b using (6-cyclobutoxy-pyridin-3-yl) carbamic acid 4-nitro-phenyl ester (Example 1 ld). 1H NMR (400 MHz, CDC1 3 ) 8 15 8.21 (s, 1H), 7.96 (d, 1H), 7.78 (dd, 1H), 7.60 (br s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.93 (br d, 1H), 6.62 (d, 1H), 5.04 (m, 1H), 4.63 (m, 1H), 4.00 (dd, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.89-3.79 (m, 3H), 2.40 (m, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.80 (m, 1H), 1.63 (m, 1H). LC/MS (ESI): calcd mass 464.2, found 465.1 (MH) . 20 EXAMPLE 45 1-(6-Cyclopentyloxy-pyridin-3-yl)-3-[1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin 3-yl]-urea (Compound No. 45) H H N N ON N' MeO NZ -N MeO N 25 155 WO 2006/135636 PCT/US2006/022142 a. 2-Cyclopentyloxy-5-nitro-pyridine 0 2 N * o ' N O 5 To a solution of 2-chloro-5-nitropyridine (7.01 g, 44.4 mmol) in THF (30 mL) and cyclopentanol (3.9 g, 45.3 mmol) was added sodium hydride (1.3 g, 54.2 mmol) portionwise with stirring over ~30 sec with ice-bath cooling at 0 oC. After stirring at 0 oC for 5 min, the ice bath was removed and the reaction was stirred at rt for 3h. It was then concentrated in vacuo and the residue was dissolved in DCM and washed 10 extensively with 1 M NaHCO 3 and then dried over anhydrous Na 2 SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 9:1 Hexane:Ethyl Acetate) to obtain pure 2 cyclopentyloxy-5-nitro-pyridine (0.4 g, 4%). 'H-NMR (300 MHz, CDC13): 8 9.07 (s, 1H), 8.32 (m, 1H), 6.74 (d, 1H), 5.53 (m, 1H), 2.00 (m, 2H), 1.81 (m, 4H), 1.66 (m, 15 2H). b. 6-Cyclopentyloxy-pyridin-3-ylamine

H

2 N 0 N O 20 To a solution of 2-cyclopentyloxy-5-nitro-pyridine (0.3099 g, 1.49 mmol), in MeOH (2 mL) was added 10% Pd/C (90 mg). The solution was degassed and was kept stirring under hydrogen atmosphere for overnight. It was filtered through a pad of celite and the filtrate was evaporated to afford the desired product as a brown oil (248 25 mg, 94% yield). 'H-NMR (300 MHz, CDCl 3 ): 8 7.69 (d, 1H), 7.04 (m, 1H), 6.56 (d, 1H), 5.25 (m, 1H), 1.93 (m, 2)), 1.28 (m, 4H), 1.60-(m, 2H). LC/MS (ESI) calcd-for

C

10 oH 1 4

N

2 0 178.23, found [M+41+1] + 220.0. c. (6-Cyclopentyloxy-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester 30 156 WO 2006/135636 PCT/US2006/022142 H 0N O N O To a solution of 6-cyclopentyloxy-pyridin-3-ylamine (0.248 g, 1.39 mmol) in THF (2 mL) was added 4-nitrophenyl chloroformate (0.280 g, 1.39 mmol) portionwise. After 5 stirring at rt for 1 h, a heavy precipitate formed in the organic layer. Filtration of the organic layer provided the title compound as a light pink solid (0.368 g, 77%). 1

H

NMR (400 MHz, CDC1 3 ): 5 11.1 (s, 1H), 9.11 (s, 1H), 9.04 (d, 1H), 8.26 (d, 2H), 7.40 (d, 2H), 7.14 (d, 1H), 5.36 (m, 1H), 2.11 (m, 2H), 1.97 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H). 10 d. 1-(6-Cyclopentyloxy-pyridin-3-yl)-3-[ 1-(6,7-dimethoxy-quinazolin-4-yl) pyrrolidin-3-yl]-urea H H NYN 0 N N MeC ' MeO N 15 Prepared essentially as described in Example 50b using (6-cyclopentyloxy-pyridin-3 yl)-carbamic acid 4-nitro-phenyl ester (Example 45c). 1H NMR (400 MHz, CDCl 3 ) 8 8.22 (s, 1H), 7.98 (d, 1H), 7.76 (dd, 1H), 7.56 (br s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.90 (br d, 1H), 6.62 (d, 1H), 5.24 (m, 1H), 4.63 (m, 1H), 4.01 (dd, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.89-3.79 (m, 3H), 2.21 (m, 2H), 1.90 (m, 2H), 1.75 (m, 4H), 1.58 (m, 20 2H). LC/MS (ESI): calcd mass 478.2, found 479.1 (MH) . EXAMPLE 46 -1-[ 11(6,7-Diffiethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(6-pyrrolidin-1-yl-pyridin-3 25 yl)-urea (Compound No. 46) 157 WO 2006/135636 PCT/US2006/022142 H H N N N MeO N MeO Nj a. (6-Pyrrolidin-1-yl-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester; 5 hydrochloride H 0 N -, HCI N/ N 0 2 N Prepared essentially as described for (4-morpholin-4-yl-phenyl)-carbamic acid 4 10 nitro-phenyl ester; hydrochloride (Example 43a) using 6-pyrrolidin-1-yl-pyridin-3 ylamine (WO 2002048152 A2). A portion was partitioned with CDC1 3 and aqueous 0.5 M trisodium citrate to generate the CDCl 3 -soluble free base: 'H-NMR (300 MHz, CDC1 3 ) 8 8.27 (min, 2H), 8.10 (d, 1H), 7.67 (dd, 1H), 7.39 (min, 2H), 6.81 (br s, 1H), 6.38 (d, 1H), 3.45 (min, 4H), 2.02 (m, 4H). LC/MS (ESI): calcd mass 328.1, found 15 329.0 (MH) . b. 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(6-pyrrolidin-1 yl-pyridin-3-yl)-urea H H '-N../ N N Y N N NN MeO -* "N MeO N 20 Prepared essentially as described for Example 16 using 4-chloro-6,7 dimethoxyquinazoline (Oakwood) and (6-pyrrolidin- 1-yl-pyridin-3-yl)-carbamic acid 4 nitro-phenyl ester; hydrochloride (Example 46a). Purified by HPLC essentially as described in Example 50b. IH NMR (400 MHz, CDC13) 8 8.37 (s, 1H), 7.98 (d, 1H), 158 WO 2006/135636 PCT/US2006/022142 7.43 (dd, 1H), 7.28 (s, 1H), 7.13 (s, 1H), 6.56 (br s, 1H), 6.29 (d, 1H), 5.56 (br s, 1H), 4.57 (m, 1H), 4.09 (dd, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.96-3.87 (m, 2H), 3.77 (dd, 1H), 3.39 (m, 4H), 2.25 (m, 1H), 2.05 (m, 1H), 1.98 ( m, 4H). LC/MS (ESI): calcd mass 463.2, found 464.1 (MH) +. 5 EXAMPLE 47 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-piperidin-1-yl-phenyl) urea (Compound No. 47) H H N N N 100 10 MeO N a. (4-Piperidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester H ON' N 15 0 2 N A solution of 4-nitrophenyl chloroformate (1.49 g, 7.39 mmol) in toluene (7.4 mL) was added in one portion to a mixture of 4-piperidin-1-yl-phenylamine (1.00 g, 5.68 mmol) (Maybridge) and CaCO 3 (739 mg, 7.39 mmol) (10 Rm powder). 20 The mixture was shaken for 5 min at rt (spontaneous warming occurred), and the resulting thick greenish opaque slurry was diluted with additional toluene (7.4 mL) and stirred for 1 hr at rt. The crude reaction was then loaded onto a silica flash column pre-equilibrated with 2.5:1 hexanes/EtQAc, and eluted with a gradient of 2.5:1 hexanes/EtOAc -+ EtOAc -4 9:1 DCM/MeOH to afford the title 25 compound as a grey powder (1.42 g, 73%). LC/MS (ESI): calcd mass 341.1, found 342.2 (MH) +. 159 WO 2006/135636 PCT/US2006/022142 b. 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-piperidin-1-yl phenyl)-urea H H N Y N MeO N MeNN Prepared essentially as described for Example 16 using 4-chloro-6,7 5 dimethoxyquinazoline (Oakwood) and (4-piperidin-1-yl-phenyl)-carbamic acid 4 nitro-phenyl ester (Example 47a). Purified by HPLC essentially as described in Example 50b. 1H NMR (400 MHz, CDC1 3 ) 8 8.36 (s, 1H), 7.27 (s, 1H), 7.13 (m, 3H), 6.85 (m, 2H), 6.41 (br s, 1H), 5.82 (br s, 1H), 4.59 (m, 1H), 4.08 (dd, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.89 (m, 2H), 3.79 (dd, 1H11), 3.08 (m, 4H), 2.24 (m, 10 1H), 2.07 (m, 1H), 1.69 (mn, 4H), 1.56 (m, 2H). LC/MS (ESI): calcd mass 476.3, found 477.1 (MH) . EXAMPLE 48 1-(4-Chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-urea 15 (Compound No. 48) H H CN N MeO- N N MeO N A solution of [1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert 20 butyl ester (55 mg, 147 gmol) (Example 35a), DMSO (112 gL), and TFA (225 PL, 3 mmol) was stirred at 100 'C for 5 min. The resulting homogeneous yellow solution was partitioned with 2.5 M NaOH (2 mL) and DCM (1 x 2 mL). The organic layer was concentrated (without previous treatment with drying agent) to give the crude amine intermediate as a yellow oil. DCM (300 gL) was added, followed by 4 25 chlorophenyl isocyanate (25 mg, 160 gmol), and the homogeneous solution was 160 WO 2006/135636 PCT/US2006/022142 stirred at rt overnight, at which point a thick white slurry resulted. The reaction was partitioned with 2 M K 2

CO

3 (2 mL) and DCM (2 mL), and the aqueous layer was extracted with 9:1 DCM/MeOH (2 x 2 mL). The combined organic layers were filtered, the filtrate was concentrated, and the residue was purified by C18 reverse 5 phase HPLC (conditions essentially as described in Example 50b). Subsequent passage through a bicarbonate solid phase extraction cartridge afforded the title compound {3.2 mg, 5% from [1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl] carbamic acid tert-butyl ester}. 1H NMR (400 MHz, 95:5 CDC1 3

/CD

3 OD) 8 8.35 (s, 1H), 7.33 (s, 1H), 7.28 (m, 2H), 7.18 (m, 2H), 7.10 (s, 1H), 4.52 (m, 1H), 4.12 (dd, 10 1H), 3.98 (s, 3H), 3.94 (s, 3H), 4.00-3.88 (m, 2H), 3.82 (dd, 1H), 2.28 (m, 1H), 2.06 (m, 1H). LC/MS (ESI): calcd mass 427.1, found 428.0 (MH) +. EXAMPLE 49 1-[1 -(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-pyrrolidin-1-yl-phenyl) 15 urea (Compound No. 49) H H N Y N N NN MeO. N MeON 20 a. (4-Pyrrolidin-l1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride H O.N 0 2 N O HCIN To a stirred solution of 4.9 g (30.4 mmol) of 4-pyrrolidin-1-yl-phenylamine in 70 mL 25 of anhydrous THF at room temperature, was added dropwise a solution of 6.4 g (32 mmol) of 4-nitrophenyl chloroformate in 16 mL of anhydrous THF. After the addition 161 WO 2006/135636 PCT/US2006/022142 was complete, the mixture was stirred for 1 h and then filtered. The precipitate was washed first with anhydrous THF (2 x 10 mL) and then with anhydrous DCM (3 x 10 mL) and dried in vacuo to yield 10 g of an off-white solid. 1 H-NMR (300 MHz,

CD

3 OD): 10.39 (s, 1H), 8.32 (d, 2H), 7.73 (d, 2H), 7.60 (d, 2H), 7.48 (d, 2H), 3.86 5 3.68 (bs, 4H), 2.35-2.24 (bs, 4H). LC/MS (ESI): 328 (MH) +. b. 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-pyrrolidin-1l-yl phenyl)-urea H H O NN MeO N MeO N 10 Prepared essentially as described for Example 50b, using (4-pyrrolidin-1-yl-phenyl) carbamic acid 4-nitro-phenyl ester hydrochloride, except 2.2 eq TEA used (42 mg, 420 pgmol). 'H NMR (400 MHz, CDC1 3 ) 8 8.44 (s, 1H), 7.35 (s, 1H), 7.18 (s, 1H), 7.03 (m, 2H), 6.48 (m, 2H), 6.11 (br s, 1H), 4.95 (br d, 1H), 4.56 (m, 1H), 4.13 (dd, 15 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.93 (t, 2H), 3.74 (dd, 1H), 3.25 (m, 4H), 2.29 (m, 1H), 2.04-1.92 (m, 5H). LC/MS (ESI): calcd mass 462.2, found 463.1 (MH) . EXAMPLE 50 1-(4-Cyclohexyl-phenyl)-3-[1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-urea 20 (Compound No. 50) H H N YN N MeO MeO N 25 a. (4-Cyclohexyl-phenyl)-carbamic acid 4-nitro-phenyl ester 162 WO 2006/135636 PCT/US2006/022142 H 0 2 N O 0 a Prepared essentially as described in Example 2a except that 4-cyclohexylaniline was used in place of 4-isopropylaniline. 'H NMR (DMSO-d 6 ) 8 10.37 (br, 1H), 8.30 (d, J 5 = 9.30 Hz, 2H), 7.52 (d, J= 9.00 Hz, 2H), 7.41 (d, J= 8.10 Hz, 2H), 7.18 (d, J= 8.70 Hz, 2H), 1.18-1.82 (11H). b. 1-(4-Cyclohexyl-phenyl)-3-[ 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3 yl]-urea 10 H H N N 0 Me(O ~ MeO N A solution of [1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert butyl ester (56 mg, 150 Rmol) (Example 35a), DMSO (112 gL), and TFA (225 gL, 3 15 mmol) was stirred at 100 oC for 5 min. The resulting homogeneous yellow solution was partitioned with 2.5 M NaOH (2 mL) and DCM (1 x 2 mL). The organic layer was concentrated (without previous treatment with drying agent) to give the crude amine intermediate as a yellow oil. This was immediately taken up in CH 3 CN (112 gL) and TEA (30 gL, 225 gmol), and treated with (4-cyclohexyl-phenyl)-carbamic 20 acid 4-nitro-phenyl ester (64 mg, 190 gmol). The mixture was stirred at 100 oC for 20 min, allowed to cool to rt, and partitioned with 2 M K 2

CO

3 (2 mL) and DCM (2 x 2 mL). The organic layers were combined, dried (Na 2

SO

4 ), and concentrated. The -residue -was -purified by -C18 reverse -phase HPLC (aq 0.1% TFA with linear increasing gradient of CH 3 CN/0.1% TFA), followed by passage through a bicarbonate 25 solid phase extraction cartridge and lyophilization to afford the title compound as a white fluffy solid { 16.4 mg, 23% from [ 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin 3-yl]-carbamic acid tert-butyl ester.} 1 H NMR (400 MHz, CDC1 3 ) 8 8.28 (s, 1H), 163 WO 2006/135636 PCT/US2006/022142 7.25-7.20 (m, 4H), 7.13-7.07 (mn, 3H), 6.44 (br s, 1H), 4.64 (br s, 1H), 4.05 (dd, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (m, 3H), 2.43 (m, 1H), 2.21 (m, 2H), 1.79 (m, 4H), 1.42-1.17 (m, 6H). LC/MS (ESI): calcd mass 475.3, found 476.1 (MH) +. 5 EXAMPLE 51 1-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-phenoxy-phenyl)-urea (Compound No. 51) H H 0 O N MeO-,h."'N 10 A mixture of 4-chloro-6,7-dimethoxyquinazoline (34 mg, 150 Rmol), 3-(tert butoxycarbonylamino)pyrrolidine (28 mg, 150 pgmol), DIEA (28 gL, 170 gmol), and DMSO (100 pL) was stirred at 100 °C for 20 min. After cooling to rt, TFA (230 gLL, 15 3.1 mmol) was added to the resulting homogeneous yellow solution, and the solution was stirred at 100 'C for 5 min. After cooling to rt, the reaction was diluted with DCM (2 mL) and washed with 2.5M NaOH (1 x 2 mL). The organic layer was collected and concentrated, dissolved in DCM (300 pL), and treated with 4 phenoxyphenyl isocyanate (34 mg, 162 gmol) at rt. After stirring overnight at rt, the 20 mixture was worked up and the title compound purified as described for Example 48. 'H NMR (400 MHz, CDC1 3 ) 8 8.26 (s, 1H), 7.40 (br s, 1H), 7.30 (m, 4H), 7.21 (s, 1H), 7.12 (s, 1H), 7.06 (m, 1H), 6.95 (m, 4H), 6.59 (br s, 1H), 4.66 (br m, 1H), 4.05 (dd, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.90 (m, 3H), 2.24 (m, 2H). LC/MS (ESI): calcd mass 485.2, found 486.1 (MH) . 25 EXAMPLE 52 1-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-dimethylamino-phenyl) urea (Compound No. 52) 164 WO 2006/135636 PCT/US2006/022142 H H N N N N MeON N MeO N N Prepared essentially as described for Example 51, using 4-(dimethylamino)phenyl 5 isocyanate. 1H NMR (400 MHz, 95:5 CDC1 3

/CD

3 OD) 8 8.41 (s, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 7.10 (m, 2H), 6.68 (m, 2H), 4.54 (m, 1H), 4.15 (dd, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.99-3.91 (m, 2H), 3.78 (dd, 1H), 2.91 (s, 3H), 2.90 (s, 3H), 2.30 (m, 1H), 2.00 (m, 1H). LC/MS (ESI): calcd mass 436.2, found 437.1 (MH)+. 10 EXAMPLE 53 1-(4-Cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl] urea (Compound No. 53) H H O NN MeO N 15 MeON N a. (4-Cyclopentyloxy-phenyl)-carbamic acid 4-nitro-phenyl ester H O N KO N O 20 Prepared essentially as described in Example 45a-c using 4-fluoronitrobenzene in place of 2-chloro-5-nitropyridine. 1H NMR (CDC1 3 ) 8 8.28 (m, 2H), 7.39 (m, 2H), 7.33 (m, 2H), 6.87 (m, 3H), 4.74 (m, 1H), 1.96-1.72 (m, 6H), 1.62 (m, 2H). 165 WO 2006/135636 PCT/US2006/022142 b. 1-(4-Cyclopentyloxy-phenyl)-3-[ 1-(6,7-dimethoxy-quinazolin-4-yl) pyrrolidin-3-yl]-urea H H N YN 0'f 0 N MeO N MeO):)N ;:j 5 Prepared essentially as described in Example 16 using 4-chloro-6,7 dimnethoxyquinazoline (Oakwood) and (4-cyclopentyloxy-phenyl)-carbamic acid 4-nitro-phenyl ester (Example 53a), and heating the nitrophenylcarbamate reaction at 80 oC in CHC1 3 instead of at 100 oC in CH 3 CN. Purified by HPLC essentially as described in Example 50b. 1H NMR (400 MHz, CDCl 3 ) 8 8.36 (s, 10 1H), 7.27 (s, 1H), 7.17 (m, 2H), 7.14 (s, 1H), 6.80 (m, 2H), 6.74 (br s, 1H), 5.80 (br d, 1H), 4.70 (m, 1H), 4.60 (m, 1H), 4.09 (dd, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.96-3.87 (m, 2H), 3.82 (dd, 1H), 2.33-2.20 (m, 1H), 2.17-2.05 (m, 1H), 1.95-1.52 (m, 8H). LC/MS (ESI): calcd mass 477.2, found 478.1 (MH) . 15 EXAMPLE 54 (4-Cyclopentyloxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) pyrrolidin-3-yl ester (Compound No. 54) H 01) 0 N MeO 'N MeO&"N 20 A mixture of 4-chloro-6,7-dimethoxyquinazoline (35 mg, 160 gmol), 3-pyrrolidinol (14 mg, 160 gmol), DMSO (100 gL), and DIPEA (30 gL, 170 gmol) was stirred at 100 'C for 5 min. The resulting homogeneous solution was allowed to cool to rt and 25 was then treated with 1.07 M KOtBu/THF (306 gL, 327 gmrol) and stirred at rt for an 166 WO 2006/135636 PCT/US2006/022142 additional ~ 1 minute. ( 4 -Cyclopentyloxy-phenyl)-carbamic acid 4-nitro-phenyl ester (64 mg, 190 gmol) (Example 53a) was then added in one portion and the resulting translucent yellow "solution" was stirred at rt for 15 min. The reaction was then worked up and purified as described in Example 48 to afford the title compound (13.9 5 mg, 19% from 4 -chloro-6,7-dimethoxyquinazoline). 'H NMR (400 MHz, CDC1 3 ) 8 8.53 (s, 1H), 7.41 (s, 1H), 7.24 (m, 3H), 6.81 (m, 2H), 6.58 (br s, 1H), 5.51 (m, 1H), 4.70 (m, 1H), 4.24 (dd, 1H), 4.15 (m, 1H), 4.06 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 2.36 (m, 1H), 2.26 (m, 1H), 1.93-1.54 (m, 8H). LC/MS (ESI): calcd mass 478.2, found 479.1 (MH) . 10 EXAMPLE 55

(

4 -Cyclopentyloxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) piperidin-4-yl ester (Compound No. 55) 00 O NO H N MeO N 15 MeO N Prepared essentially as described in Example 54 using 4-hydroxypiperidine in place of 3-pyrrolidinol. 'H NMR (400 MHz, CDC1 3 ) 8 8.68 (s, 1H), 7.30-7.24 (m, 3H), 20 7.10 (s, 1H), 6.83 (m, 2H), 6.49 (br s, 1H), 5.08 (m, 1H), 4.72 (m, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 3.93 (m, 2H), 3.51 (m, 2H), 2.18 (m, 2H), 2.00-1.73 (m, 8H), 1.61 (m, 2H). LC/MS (ESI): calcd mass 492.2, found 493.1 (MH) . 25 EXAMPLE 56

(

4 -Cyclopentyloxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) piperidin-4-ylmethyl ester (Compound No. 56) 167 WO 2006/135636 PCT/US2006/022142 H 0 0 N MeON N MeO N Prepared essentially as described for Example 54 using 4-piperidinemethanol in place 5 of 3-pyrrolidinol. 'H NMR (400 MHz, CDCl 3 ) 8 8.67 (s, 1H), 7.30-7.23 (m, 3H), 7.09 (s, 1H), 6.83 (m, 2H), 6.49 (br s, 1H), 4.72 (m, 1H), 4.22 (m, 2H), 4.12 (d, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.08 (m, 2H), 2.05 (m, 1H), 1.99-1.73 (m, 7H), 1.67-1.52 (m, 5H). LC/MS (ESI): calcd mass 506.2, found 507.1 (MH) +. 10 EXAMPLE 57 (4-Cyclopentyloxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl) piperidin-3-ylmethyl ester (Compound No. 57) 0~~ O NO H MeO N N MeO N 15 Prepared essentially as described for Example 54 using 3-piperidinemnethanol in place of 3-pyrrolidinol. Following HPLC purification, the title compound was further purified by silica flash chromatography (9:2 EtOAc/acetone eluent). 1H NMR (400 MHz, CDC3) 6167(- s, 1H), 7.28-7.22 (m, 2H), 7.23 (s, 1H), 7.10 (s, 1H), 6.81 (m, 20 2H), 6.65 (br s, 1H), 4.71 (m, 1H), 4.25 (dd, 1H), 4.19 (m, 1H), 4.09-3.97 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.08 (m, 1H), 2.92 (dd, 1H), 2.28 (m, 1H), 2.03-1.71 (m, 9H), 1.60 (m, 2H), 1.48 (m, 1H). LC/MS (ESI): calcd mass 506.2, found 507.3

(MH)

+. 168 WO 2006/135636 PCT/US2006/022142 EXAMPLE 58 1- [-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4-isopropoxy-phenyl)-urea (Compound No. 58) O N NH H (N MeO N 5 MeO N-y Prepared essentially as described in Example 16 using 4-chloro-6,7 dimethoxyquinazoline (Oakwood), piperidin-4-yl-carbamic acid tert-butyl ester (TCI America), and ( 4 -isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (Example 32a). Purified by HPLC essentially as described in Example 50b. 1 H NMR (400 10 MHz, CDC1 3 ) 8 8.64 (s, 1H), 7.23 (s, 1H), 7.15 (m, 2H), 7.05 (s, 1H), 6.87 (mn, 2H11), 6.00 (br s, 1H), 4.55-4.48 (min, 2H), 4.10 (min, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 4.04 (inm, 1H), 3.25 (min, 2H), 2.14 (m, 2H), 1.59 (min, 2H), 1.34 (d, 6H). LC/MS (ESI): calcd mass 465.2, found 466.1 (MH) +. 15 EXAMPLE 59 1-[ 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4-morpholin-4-yl-phenyl) urea (Compound No. 59) 0 N~N NN NH H N MeO N MeO N 20 Prepared essentially as described in Example 16 using 4-chloro-6,7 dimethoxyquinazoline (Oakwood), piperidin-4-yl-carbamic acid tert-butyl ester (TCI 169 WO 2006/135636 PCT/US2006/022142 America), and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester (Example 43b). Purified by HPLC essentially as described in Example 50b. 'H NMR (400 MHz, 95:5 CDC1 3

/CD

3 OD) 8 8.62 (s, 1H), 7.22 (s, 1H), 7.18 (m, 2H), 7.06 (s, 1H), 6.90 (m, 2H), 4.10 (m, 2H), 4.05-3.98 (m, 1H), 4.02 (s, 3H), 3.98 (s, 3H), 3.86 5 (m, 4H), 3.27 (m, 2H), 3.14 (m, 4H), 2.13 (m, 2H), 1.59 (m, 2H). LC/MS (ESI): calcd mass 492.2, found 493.1 (MH) +. EXAMPLE 60 1-[I-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4-pyrrolidin-1-yl-phenyl) 10 urea (Compound No. 60) N NH H N MeO MeO) --N'y Prepared essentially as described in Example 16 using 4-chloro-6,7 dimethoxyquinazoline (Oakwood), piperidin-4-yl-carbamic acid tert-butyl ester (TCI America), and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester 15 hydrochloride (Example 49a). Purified by HPLC essentially as described in Example 50b. 1H NMR (400 MHz, CDC1 3 ) 5 8.63 (s, 1H), 7.22 (s, 1H), 7.07 (m, 2H), 7.04 (s, 1H), 6.52 (m, 2H), 5.86 (br s, 1H), 4.50 (br d, 1H), 4.07 (m, 2H), 4.03-4.00 (m, 1H), 4.01 (s, 3H), 3.97 (s, 3H), 3.31-3.19 (m, 6H), 2.11 (m, 2H), 2.02 (m, 4H), 1.60-1.50 (m, 2H). LC/MS (ESI): calcd mass 476.2, found 477.1 (MH) +. 20 EXAMPLE 61 1-(4-Chloro-phenyl)-3-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-urea (Compound Nb. 61) 170 WO 2006/135636 PCT/US2006/022142 a 0 Nk N NH H N MeO ed N MeO 'N N Prepared essentially as described in Example 51 using piperidin-4-yl-carbamic acid tert-butyl ester (TCI America) and 4-chlorophenyl isocyanate. H NMR (400 MHz, 5 95:5 CDC1 3

/CD

3 OD) 8 8.57 (s, 1H), 7.33 (m, 2H), 7.22 (m, 2H), 7.20 (s, 1H), 7.10 (s, 1H), 4.06 (m, 2H), 4.04 (s, 3H), 4.03-3.96 (m, 1H), 4.00 (s, 3H), 3.39 (m, 2H), 2.14 (m, 2H), 1.66 (m, 2H). LC/MS (ESI): calcd mass 441.2, found 442.1 (MH) +. EXAMPLE 62 10 1- [1-( 6 ,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4-dimethylamino-phenyl) urea (Compound No. 62) O. N NH H N MeO& N MeO 'N N - ' Prepared essentially as described in Example 51 using piperidin-4-yl-carbamic acid 15 tert-butyl ester (TCI America) and 4-(dimethylamino)phenyl isocyanate. 'H NMR (400 MHz, CDC1 3 ) 8 8.64 (s, 1H), 7.22 (s, 1H), 7.10 (br m, 2H), 7.05 (s, 1H), 6.70 (br m, 2H), 5.97 (br s, 1H), 4.55 (br m, 1H), 4.09 (m,_2H), 4.05-3.95 (m, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 3.24 (m, 2H), 2.96 (br s, 6H), 2.12 (m, 2H), 1.55 (m, 2H). LC/MS (ESI): calcd mass 450.2, found 451.2 (MH) . 20 EXAMPLE 63 171 WO 2006/135636 PCT/US2006/022142 1-(4-Isopropyl-phenyl)-3-(1-quinazolin-4-yl-piperidin-4-yl)-urea (Compound No. 63) 0 N-t NH H N N Essentially as described in Example 16 using piperidin-4-yl-carbamic acid tert-butyl ester in place of 3-(tert-butoxycarbonylamino)pyrrolidine. Purified by HPLC 5 essentially as described in Example 50b. 'H NMR (400 MHz, CDC1 3 ) 6 8.71 (s, 1H), 7.86 (dd, 2H), 7.73 (min, 1H), 7.45 (m, 1H), 7.21-7.16 (m, 4H), 6.36 (br s, 1H), 4.79 (br d, 1H), 4.29 (m, 2H), 4.06 (min, 1H), 3.30 (min, 2H), 2.88 (heptet, 1H), 2.15 (mn, 2H), 1.59 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 389.2, found 390.2 (MH) . 10 EXAMPLE 64 1-(4-Isopropyl-phenyl)-3-[1-(6-methoxy-quinazolin-4-yl)-piperidin-4-yl]-urea (Compound No. 64) 0 N-' NH H N MeO ~ N Prepared essentially as described in Example 16 using 4-chloro-6 15 methoxyquinazoline (WO 2001032632 A2, WO 9609294 Al) and piperidin-4-yl carbamic acid tert-butyl ester. Purified by HPLC essentially as described in Example 50b. IHNMR (400 MHz, CDC13)--8.66 (s;- 1H), 7.83-(d,1H), 7.40 (dd, 1H), 7.18 (m, 4H), 7.10 (d, 1H), 6.45 (br s, 1H), 4.85 (br d, 1H), 4.18 (m, 2H), 4.05 (m, 1H), 3.90 (s, 3H), 3.27 (min, 2H), 2.88 (heptet, 1H), 2.15 (m, 2H), 1.60 (mn, 2H), 1.22 (d, 6H). 20 LC/MS (ESI): calcd mass 419.2, found 420.2 (MH) +. 172 WO 2006/135636 PCT/US2006/022142 EXAMPLE 65 1-(4-Isopropyl-phenyl)-3-[1-(7-methoxy-quinazolin-4-yl)-piperidin-4-yl]-urea (Compound No. 65) O N NH H N ~ N MeON 5 Prepared essentially as described in Example 74b using methanol in place of 1-(2 hydroxy-ethyl)-pyrrolidin-2-one. H NMR (400 MHz, CDC1 3 ) 5 8.65 (s, 1H), 7.73 (d, 1H), 7.22-7.15 (m, 5H), 7.06 (dd, 1H), 6.16 (br s, 1H), 4.66 (br d, 1H), 4.23 (m, 2H), 4.05 (m, 1H), 3.93 (s, 3H), 3.28 (m, 2H), 2.89 (heptet, 1H), 2.15 (m, 2H), 1.60 10 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 419.2, found 420.2 (MH) . EXAMPLE 66 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4-isopropyl-phenyl)-urea (Compound No. 66) 0 N NH H N MeO N 15 MeO N Prepared essentially as described in Example 16 using 4-chloro-6,7 dimethoxyquinazoline and piperidin-4-yl-carbamnic acid tert-butyl ester. Purified by HPLC essentially as described in Example 50b. 1H NMR (400 MHz, CDCl 3 ) 8 8.64 (s, 1H), 7.22 (s, 1H), 7.19 (s, 4H), 7.06 (s, 1H), 6.48 (br s, 1H), 4.86 (br d, 1H), 4.12 20 (m, 2H), 4.07-4.01 (m, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.26 (m, 2H), 2.88 (heptet, 173 WO 2006/135636 PCT/US2006/022142 1H), 2.15 (m, 2H), 1.60 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 449.2, found 450.1 (MH) +. EXAMPLE 67 5 1-(4-Cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl] urea (Compound No. 67) O N NH H N MeO - N MeO , N 10 Prepared essentially as described in Example 16 using 4-chloro-6,7 dimethoxyquinazoline, piperidin-4-yl-carbamic acid tert-butyl ester, and (4 cyclopentyloxy-phenyl)-carbamic acid 4-nitro-phenyl ester. Purified by HPLC essentially as described in Example 50b. 1H NMR (400 MHz, 95:5 CDCl 3

/CD

3 OD) 8 8.57 (s, 1H), 7.34 (s, 1H), 7.18 (m, 2H), 7.06 (s, 1H), 6.81 (m, 2H), 4.70 (min, 1H), 4.26 15 (m, 2H), 4.07-4.00 (s, 1H), 4.04 (s, 3H), 3.98 (s, 3H), 3.39 (m, 2H), 2.14 (m, 2H), 1.94-1.72 (m, 6H), 1.61 (m, 4H). LC/MS (ESI): calcd mass 491.2, found 492.1

(MH)

+. EXAMPLE 68 20 1-[1-(6,7-Dimnethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(6-pyrrolidin-1-yl-pyridin-3 yl)-urea (Compound No. 68) N NH H N MeO -N 174 WO 2006/135636 PCT/US2006/022142 Prepared essentially as described in Example 16 using 4-chloro-6,7 dimethoxyquinazoline (Oakwood), piperidin-4-yl-carbamic acid tert-butyl ester (TCI America), and (6-Pyrrolidin-1-yl-pyridin-3-yl)-carbamic acid 4-nitro-phenyl ester; 5 hydrochloride (Example 46a). Purified by filtration of the crude final reaction mixture to afford the pure title compound as an off-white powder (36.1 mg, 50% from 4-chloro-6,7-dimethoxyquinazoline). 1H NMR (400 MHz, DMSO-d6) 8 8.51 (s, 1H), 7.98 (d, 1H11), 7.92 (s, 1H), 7.54 (dd, 1H), 7.19 (s, 1H), 7.10 (s, 1H11), 6.35 (d, 1H), 6.13 (d, 1H), 4.03 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.75 (m, 1H), 3.30 (m, 4H), 3.22 (m, 10 2H), 1.97 (m, 2H), 1.90 (m, 4H), 1.59 (m, 2H11). LC/MS (ESI): calcd mass 477.2, found 478.2 (MH) . EXAMPLE 69 1-[1-(7-Fluoro-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl-phenyl)-urea 15 (Compound No. 69) H H N N I 0 N F N Isolated in a separate fraction from the Example 70 title compound during HPLC purification of the latter (see Example 70b). 1 H NMR (400 MHz, CDC1 3 ) 8 8.42 (s, 20 1H), 8.03 (dd, 1H), 7.38 (dd, 1H), 7.21-7.13 (m, 4H11), 7.10 (ddd, 1H), 6.71 (br s, 1H), 5.89 (br d, 1H), 4.63 (m, 1H), 4.15 (dd, 1H11), 4.00-3.88 (m, 2H), 3.85 (dd, 1H11), 2.86 (heptet, 1H), 2.35-2.25 (m, 1H), 2.16 (m, 1H), 1.21 (d, 6H). LC/MS (ESI): calcd mass 393.2, found 394.2 (MH) . 25 EXAMPLE 70 1 -(4-Isopropyl-phenyl)-3-(1- { 7-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl } pyrrolidin-3-yl)-urea (Compound No. 70) 175 WO 2006/135636 PCT/US2006/022142 H H N N N ON a. [1-(7-Fluoro-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl 5 ester BocHN N FN A vial was charged with 4-chloro-7-fluoro-quinazoline (2.00 g, 11.0 mmol) (WO 10 9609294 Al), pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.05 g, 11.0 mmol), DMSO (2.64 mL), and DIPEA (2.10 mL, 12.0 mmol) in quick succession. The mixture was stirred at "rt" for 20 min, during which time the reaction spontaneously warmed and became a homogeneous reddish-brown solution. The reaction was then stirred at 100 oC for 2.5 min to ensure complete reaction. The 15 solution was shaken with water (20 mL) to dissolve the DMSO into the aqueous phase, and was extracted with EtOAc (1 x 20 mL). The organic layer was washed with 4 M NaC1 (1 x 20 mL) and dried (Na 2

SO

4 ). Upon addition of Na 2

SO

4 to the organic phase, the title compound began to precipitate out. This was collected by filtration (easily decanted from the wet drying agent), dried, and powdered to 20 afford the title compound as an off-white powder (1.42 g, 39%). b. 1-(4-Isopropyl-phenyl)-3-(1- {7-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinazolin 4-yl } -pyrrolidin-3-yl)-urea 176 WO 2006/135636 PCT/US2006/022142 H H N N 0 N NON O A mixture of 1-(2-hydroxy-ethyl)-pyrrolidin-2-one (50.8 mg, 394 pgmol), KOtBu (41 mg, 366 gmol), DMSO (300 pL), and [1-(7 fluoro-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (103 mg, 310 gmol) was stirred at 100 oC for 20 min and then allowed the cool to rt. The 5 reaction was then partitioned with water (4 mL) and 9:1 DCM/MeOH (2 x 4 mL). The organic layers were combined, dried (Na 2 SO4), and concentrated. The residue (104 mg crude SNAr product) was taken up in TFA (182 gL, 2.4 mmol) and CHC1 3 (180 gL), and was stirred in a sealed vial at 100 °C for 10 min. The reaction was then allowed to cool to rt and was partitioned between 2.5 M NaOH 10 (2 mL) and 9:1 DCM/MeOH (2 x 4 mL). The combined organic layers were dried (Na 2 SO4), filtered, and concentrated. The residue (91 mg crude amine) was taken up in CHC1 3 (600 pL), TEA (41 gL, 294 gmol), and (4-isopropyl-phenyl) carbamic acid 4-nitro-phenyl ester (88 mg, 293 pmol) and was stirred at 100 oC for 10 min. After cooling to rt, the reaction was partitioned with 2.5 M NaOH (2 15 mL) and DCM (1 x 4 mL, 1 x 2 mL), the organic layers were combined, dried (Na 2

SO

4 ), filtered, and concentrated. The residue was dissolved in 90:10:1 v/v MeOH/water/TFA and purified by C18 reverse phase HPLC (water/CH 3 CN/0.1% TFA -- + increasing CH 3 CN/0.1% TFA). The TFA was removed via passage through a bicarbonate solid phase extraction cartridge and the product further 20 purified by silica flash chromatography (95:5 DCM/MeOH eluent) to afford the title compound { 5.6 mg, 3.6% from [1-(7-Fluoro-quinazolin-4-yl)-pyrrolidin-3 yl]-carbamic acid tert-butyl ester}. 1 H NMR (400 MHz, CDCl 3 ) 8 8.31 (s, 1H), 7.78 (d, 1H), 7.55 (br s, 1H), 7.25 (m, 2H), 7.11 (m, 2H), 7.00 (d, 1H), 6.85 (dd, 1H), 6.49 (br d, 1H), 4.58 (m, 1H), 4.12 (t, 2H), 4.05 (dd, 1H), 3.89-3.76 (m, 2H), 25 3.76-3.67 (m, 3H), 3.54 (t, 2H), 2.83 (heptet, 1H), 2.42 (t, 2H), 2.22 (m, 1H), 2.14-2.01 (m, 3H), 1.20 (d, 6H). LC/MS (ESI): calcd mass 502.3, found 503.2 (MH)*. 177 WO 2006/135636 PCT/US2006/022142 EXAMPLE 71 1-(4-Isopropyl-phenyl)-3-{ 1-[7-(2-methoxy-ethoxy)-quinazolin-4-yl]-pyrrolidin-3 yl}-urea (Compound No. 71) 5 H H ON A<N N N Prepared essentially as described in Example 70b using 2-methoxyethanol in place of 10 1-(2-hydroxy-ethyl)-pyrrolidin-2-one. 1H NMR (400 MHz, CDC1 3 ) 8 8.30 (s, 1H), 7.81 (d, 1H), 7.23 (m, 2H), 7.20 (br s, 1H), 7.12 (m, 2H), 7.06 (d, 1H), 6.96 (dd, 1H), 6.40 (br s, 1H), 4.62 (m, 1H), 4.16 (m, 2H), 4.05 (dd, 1H), 3.91-3.76 (m, 5H), 3.46 (s, 3H), 2.85 (heptet, 1H), 2.29-2.11 (m, 2H), 1.20 (d, 6H). LC/MS (ESI): calcd mass 449.2, found 450.1 (MH) . 15 EXAMPLE 72 1-[1-(7-Fluoro-quinazolin-4-yl)-piperidin-4-yl]-3-(4-isopropyl-phenyl)-urea (Compound No. 72) N NH H N -. '~N 20 F N 178 WO 2006/135636 PCT/US2006/022142 Isolated in a separate fraction from the Example 75 title compound during HPLC purification of the latter (see Example 75). 'H NMR (400 MHz, CDC13) 8 8.68 (s, 1H), 7.85 (dd, 1H11), 7.49 (dd, 1H), 7.23-7.15 (m, 5H), 6.22 (br s, 1H), 4.69 (br d, 1H), 4.27 (m, 2H), 4.06 (m, 1H), 3.31 (m, 2H), 2.89 (heptet, 1H), 2.15 (m, 2H), 1.58 (m, 5 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 407.2, found 408.2 (MH)*. EXAMPLE 73 1-(4-Isopropyl-phenyl)-3- { 1- [7-(2-methoxy-ethoxy)-quinazolin-4-yl]-piperidin-4-yl } urea (Compound No. 73) 10 N NH H N N Prepared essentially as described in Example 74b using 2-methoxyethanol in place of 1-(2-hydroxy-ethyl)-pyrrolidin-2-one. 1H NMR (400 MHz, CDC1 3 ) 5 8.64 (s, 1H), 7.73 (d, 1H11), 7.22-7.15 (m, 5H), 7.11 (dd, 1H), 6.17 (br s, 1H11), 4.67 (br d, 1H11), 4.27 15 4.19 (m, 4H), 4.05 (m, 1H11), 3.82 (m, 2H11), 3.47 (s, 3H), 3.27 (m, 2H), 2.89 (heptet, 1H), 2.15 (m, 2H11), 1.59 (m, 2H11), 1.23 (d, 6H). LC/MS (ESI): calcd mass 463.3, found 464.2 (MH) . EXAMPLE 74 20 1-(4-Isopropyl-phenyl)-3-(1- {7-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl} piperidin-4-yl)-urea (Compound No. 74) 179 WO 2006/135636 PCT/US2006/022142 N NH H N N~ a. [1-(7-Fluoro-quinazolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester NHBoc N .- N F N 5 Prepared essentially as described in Example 70a using piperidin-4-yl-carbamic acid tert-butyl ester in place of pyrrolidin-3-yl-carbamic acid tert-butyl ester, except after stirring at 100 oC for 2.5 min, the homogeneous solution was stirred at rt for 5 hrs. Also, aqueous workup yielded the title compound as an amber oil 10 rather than as a precipitated solid (2.8 g, 84%). 1 H NMR (CDC1 3 ) 8 8.70 (s, 1H), 7.86 (dd, 1H), 7.50 (dd, 1H), 7.21 (dd, 1H), 4.55 (br d, 1H), 4.25 (m, 2H), 3.80 (br m, 1IH), 3.27 (m, 2H), 2.13 (m, 2H), 1.61 (m, 2H), 1.46 (s, 9H). b. 1-(4-Isopropyl-phenyl)-3-(1-{7-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinazolin 15 4-yl } -piperidin-4-yl)-urea 0 N NH H N 0 N 18 180 WO 2006/135636 PCT/US2006/022142 A mixture of 1-(2-hydroxy-ethyl)-pyrrolidin-2-one (51 mg, 400 Rmol), KOtBu (41 mg, 370 Rmol), DMSO (150 gLL), and [1-(7-fluoro-quinazolin-4-yl)-piperidin 4-yl]-carbamic acid tert-butyl ester (110 mg, 310 pmol) was stirred at 100 'C for 40 min and then allowed the cool to rt. The reaction was then partitioned with 5 water (4 mL) and 9:1 DCM/MeOH (2 x 4 mL). The organic layers were combined, dried (Na 2 SO4), and concentrated. The residue (crude SNAr product) was taken up in TFA (180 gL, 2.4 mmol) and CHC1 3 (180 pL), and was stirred in a sealed vial at 100 oC for 10 min. The reaction was then allowed to cool to rt and was partitioned between 2.5 M NaOH (2 mL) and 9:1 DCM/MeOH (2 x 4 mL). 10 The combined organic layers were dried (Na 2

SO

4 ), filtered, and concentrated. The residue (crude amine) was taken up in DCM (600 gL), TEA (41 pL, 290 gmol), and (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (88 mg, 290 pmol) and was stirred at 40 'C for 2 hr. After cooling to rt, the reaction was partitioned with 2.5 M NaOH (2 mL) and DCM (1 x 4 mL, 1 x 2 mL), the organic 15 layers were combined, dried (Na 2 SO4), filtered, and concentrated. The residue was dissolved in 90:10:1 v/v MeOH/water/TFA and purified by C18 reverse phase HPLC (water/CH 3 CN/0.1% TFA -- increasing CH 3 CN/0.1% TFA). The TFA was removed via passage through a bicarbonate solid phase extraction cartridge to afford the title compound { 10.8 mg, 7% from [1-(7-fluoro-quinazolin-4-yl) 20 piperidin-4-yl]-carbamic acid tert-butyl ester}.

1 H NMR (400 MHz, CDC1 3 ) 5 8.63 (s, 1H), 7.73 (d, 1H), 7.22-7.15 (m, 5H), 7.03 (dd, 1H), 6.23 (br s, 1H), 4.73 (br d, 1H), 4.23 (m, 4H11), 4.05 (m, 1H), 3.76 (t, 2H), 3.58 (t, 2H), 3.29 (m, 2H), 2.89 (heptet, 1H), 2.41 (t, 2H), 2.14 (m, 2H), 2.05 (m, 2H), 1.60 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 516.3, found 517.2 (MH)

+

. 25 EXAMPLE 75 1-(4-Isopropyl-phenyl)-3-(1- { 7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4 yl}-piperidin-4-yl)-urea (Compound No. 75) 30 181 WO 2006/135636 PCT/US2006/022142 0 N NH H N NON Prepared essentially as described in Example 74b using 3 -(4-methyl-piperazin-1-yl) propan-l-ol in place of 1-(2-hydroxy-ethyl)-pyrrolidin-2-one. 'H NMR (400 MHz, CDC13) 8 8.63 (s, 1H), 7.72 (d, 1H), 7.22-7.14 (m, 5H), 7.04 (dd, 1H), 6.25 (br s, 1H), 5 4.75 (br d, 1H), 4.22 (m, 2H), 4.14 (t, 2H), 4.04 (m, 1H), 3.27 (m, 2H), 2.88 (heptet, 1H), 2.70-2.32 (m, 10H), 2.30 (s, 3H), 2.14 (m, 2H), 2.03 (m, 2H), 1.57 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 545.3, found 546.3 (MH) +. 182 WO 2006/135636 PCT/US2006/022142 BIOLOGICAL ACTIVITY OF FLT3 INHIBITORS OF FORMULA I' The following representative assays were performed in determining the biological 5 activities of the FLT3 inhibitors of Formula I'. They are given to illustrate the invention in a non-limiting fashion. In Vitro Assays 10 The following representative in vitro assays were performed in determining the biological activities of the FLT3 inhibitors of Formula I' within the scope of the invention. They are given to illustrate the invention in a non-limiting fashion. Inhibition of FLT3 enzyme activity, MV4-11 proliferation and Baf3-FLT3 15 phosphorylation exemplify the specific inhibition of the FLT3 enzyme and cellular processes that are dependent on FLT3 activity. Inhibition of Baf3 cell proliferation is used as a test of FLT3, c-Kit and TrkB independent cytotoxicity of compounds within the scope of the invention. All of the examples herein show significant and specific inhibition of the FLT3 kinase and FLT3-dependent cellular responses. Examples 20 herein also show specific inhibition of the TrkB and c-kit kinase in an enzyme activity assay. The FLT3 inhibitor compounds are also cell permeable. FLT3 Fluorescence Polarization Kinase Assay 25 To determine the activity of the FLT3 inhibitors of Formula I' in an in vitro kinase assay, inhibition of the isolated kinase domain of the human FLT3 receptor (a.a. 571 993) was performed using the following fluorescence polarization (FP) protocol. The FLT3 FP assay utilizes the fluorescein-labeled phosphopeptide and the anti phosphotyrosine antibody included in the Panvera Phospho-Tyrosine Kinase Kit 30 (Green) supplied by Invitrogen. When FLT3 phosphorylates polyGlu4Tyr, the fluorescein-labeled phosphopeptide is displaced from the anti-phosphotyrosine antibody by the phosphorylated poly Glu4Tyr, thus decreasing the FP value. The FLT3 kinase reaction is incubated at room temperature for 30 minutes under the 183 WO 2006/135636 PCT/US2006/022142 following conditions: 0lnM FLT3 571-993, 20ug/mL poly Glu4Tyr, 150uM ATP, 5mM MgC12, 1% compound in DMSO. The kinase reaction is stopped with the addition of EDTA. The fluorescein-labeled phosphopeptide and the anti phosphotyrosine antibody are added and incubated for 30 minutes at room 5 temperature. All data points are an average of triplicate samples. Inhibition and IC 50 data analysis was done with GraphPad Prism using a non-linear regression fit with a multiparamater, sigmoidal dose-response (variable slope) equation. The IC 50 for 10 kinase inhibition represents the dose of a compound that results in a 50% inhibition of kinase activity compared to DMSO vehicle control. Inhibition Of MV4-11 and Baf3 Cell Proliferation 15 To assess the cellular potency of the FLT3 inhibitors of Formula I', FLT3 specific growth inhibition was measured in the leukemic cell line MV4-11 (ATCC Number: CRL-9591). MV4-11 cells are derived from a patient with childhood acute myelomonocytic leukemia with an 1 1q23 translocation resulting in a MLL gene rearrangement and containing an FLT3-ITD mutation (AML subtype M4)(see Drexler 20 HG. The Leukemia-Lymphoma Cell Line Factsbook. Academic Pres: San Diego, CA, 2000 and Quentmeier H, Reinhardt J, Zaborski M, Drexler HG. FLT3 mutations in acute myeloid leukemia cell lines. Leukemia. 2003 Jan;17:120-124.). MV4-11 cells cannot grow and survive without active FLT3ITD. 25 The IL-3 dependent, murine b-cell lymphoma cell line, Baf3, were used as a control to confirm the selectivity of the FLT3 inhibitor compounds by measuring non-specific growth inhibition by the FLT3 inhibitor compounds. To measure proliferation inhibition by test compounds, the luciferase based -- 30 -CellTiterGlo-re-get-(Prt6iega), which quiantifies total cell nu-mber based on total cellular ATP concentration, was used. Cells are plated at 10,000 cells per well in 100ul of in RPMI media containing penrn/strep, 10% FBS and Ing/ml GM-CSF or lng/ml IL-3 for MV4-11 and Baf3 cells respectively. 184 WO 2006/135636 PCT/US2006/022142 Compound dilutions or 0.1% DMSO (vehicle control) are added to cells and the cells are allowed to grow for 72 hours at standard cell growth conditions (37 oC, 5%CO 2 ). For activity measurements in MV4-11 cells grown in 50% plasma, cells were plated at 5 10,000 cells per well in a 1:1 mixture of growth media and human plasma (final volume of 100 pL). To measure total cell growth an equal volume of CellTiterGlo reagent was added to each well, according to the manufacturer's instructions, and luminescence was quantified. Total cell growth was quantified as the difference in luminescent counts (relative light units, RLU) of cell number at Day 0 compared to 10 total cell number at Day 3 (72 hours of growth and/or compound treatment). One hundred percent inhibition of growth is defined as an RLU equivalent to the Day 0 reading. Zero percent inhibition was defined as the RLU signal for the DMSO vehicle control at Day 3 of growth. All data points are an average of triplicate samples. The

IC

50 for growth inhibition represents the dose of a compound that results in a 50% 15 inhibition of total cell growth at day 3 of the DMSO vehicle control. Inhibition and

IC

50 data analysis was done with GraphPad Prism using a non-linear regression fit with a multiparamater, sigmoidal dose-response (variable slope) equation. MV4-11 cells express the FLT3 internal tandem duplication mutation, and thus are 20 entirely dependent upon FLT3 activity for growth. Strong activity against the MV4 11 cells is anticipated to be a desirable quality of the invention. In contrast, the Baf3 cell proliferation is driven by the cytokine EL-3 and thus are used as a non-specific toxicity control for test compounds. All compound examples in the present invention showed < 50% inhibition at a 3uM dose (data is not included), suggesting that the 25 compounds are not cytotoxic and have good selectivity for FLT3. Cell-Based FLT3 Receptor Elisa Specificcellular inhibition ofFLTligand-induced wild-type FLT3-phosphorylatiot 30 was measured in the following manner: Baf3 FLT3 cells overexpressing the FLT3 receptor were obtained from Dr. Michael Heinrich (Oregon Health and Sciences University). The Baf3 FLT3 cell lines were created by stable transfection of parental Baf3 cells (a murine B cell lymphoma line dependent on the cytokine IL-3 for 185 WO 2006/135636 PCT/US2006/022142 growth) with wild-type FLT3. Cells were selected for their ability to grow in the absence of IL-3 and in the presence of FLT3 ligand. Baf3 cells were maintained in RPMI 1640 with 10% FBS, penn/strep and 10ng/ml 5 FLT ligand at 37 'C, 5%CO2. To measure direct inhibition of the wild-type FLT3 receptor activity and phosphorylation a sandwich ELISA method was developed similar to those developed for other RTKs (see Sadick, MD, Sliwkowski, MX, Nuijens, A, Bald, L, Chiang, N, Lofgren, JA, Wong WLT. Analysis of Heregulin Induced ErbB2 Phosphorylation with a High-Throughput Kinase Receptor Activation 10 Enzyme-Linked Immunsorbent Assay, Analytical Biochemistry. 1996; 235:207-214 and Baumann CA, Zeng L, Donatelli RR, Maroney AC. Development of a quantitative, high-throughput cell-based enzyme-linked immunosorbent assay for detection of colony-stimulating factor-1 receptor tyrosine kinase inhibitors. J Biochem Biophys Methods. 2004; 60:69-79.). 200pL of Baf3FLT3 cells (1x10 6 /mL) were 15 plated in 96 well dishes in RPMI 1640 with 0.5% serum and 0.01ng/mL IL-3 for 16 hours prior to 1 hour compound or DMSO vehicle incubation. Cells were treated with 100Ong/mL Fit ligand (R&D Systems Cat# 308-FK) for 10 min. at 37 'C. Cells were pelleted, washed and lysed in 100ul lysis buffer (50 mM Hepes, 150 mM NaC1, 10% Glycerol, 1% Triton -X-100, 10 mM NaF, 1 mM EDTA, 1.5 mM MgCl 2 , 10 mM 20 NaPyrophosphate) supplemented with phosphatase (Sigma Cat# P2850) and protease inhibitors (Sigma Cat #P8340). Lysates were cleared by centrifugation at 1000xg for 5 minutes at 4 oC. Cell lysates were transferred to white wall 96 well microtiter (Costar #9018) plates coated with 50ng/well anti-FLT3 antibody (Santa Cruz Cat# sc 480) and blocked with SeaBlock reagent (Pierce Cat#37527). Lysates were incubated 25 at 4 oC for 2 hours. Plates were washed 3x with 200ul/well PBS/0.1% Triton-X-100. Plates were then incubated with 1:8000 dilution of HRP-conjugated anti phosphotyrosine antibody (Clone 4G10, Upstate Biotechnology Cat#16-105) for 1 hour at room temperature. Plates were washed 3x with 200ul/well PBS/0.1% Triton X-100. -Signal detection -with Super Signal Pico reag int-(Pieice-Ci t#37070) was clone 30 according to manufacturer's instruction with a Berthold microplate luminometer. All data points are an average of triplicate samples. The total relative light units (RLU) of Flt ligand stimulated FLT3 phosphorylation in the presence of 0.1% DMSO control was defined as 0% inhibition and 100% inhibition was the total RLU of lysate in the 186 WO 2006/135636 PCT/US2006/022142 basal state. Inhibition and IC 5 0 data analysis was done with GraphPad Prism using a non-linear regression fit with a multiparamater, sigmoidal dose-response (variable slope) equation. 5 BIOLOGICAL DATA Biological Data for FLT3 The activity of representative FLT3 inhibitor compounds is presented in the charts 10 hereafter. All activities are in pM and have the following uncertainties: FLT3 kinase: +10%; MV4-11 and Baf3-FLT3: + 20%. FLT3 MV4-11 BaF3 No. Compound Name Kinase (uM) ELISA (uM) (uM) 1 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy- 0.006 0.181 0.016 quinazolin-4-yl)-piperidin-4-yl ester 2 (4-1sopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy- 0.007 0.248 0.064 quinazolin-4-yl)-pyrrolidin-3-yl ester 3 (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy- 0.008 0.467 0.118 quinazolin-4-yl)-piperidin-4-yl ester 4 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy- 0.011 0.086 0.006 quinazolin-4-yl)-piperidin-3-ylmethyl ester 5 2-[1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-N-(4- 0.012 0.007 0.006 isopropyl-phenyl)-acetamide 6 2-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-N-(4- 0.014 0.008 0.046 isopropyl-phenyl)-acetamide 7 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4- 0.016 0.909 0.14 isopropyl-phenyl)-urea 8 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4- 0.023 1.88 0.36 isopropoxy-phenyl)-urea 9 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy- 0.025 0.196 0.027 quinazolin-4-yl)-pyrrolidin-2-ylmethyl ester 10 (4-1sopropyl-phenyl)-carbamic acid 1-quinolin-4-yl-piperidin- 0.026 1.1 nd 4-yl ester 11 (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-(6,7-dimethoxy- 0.028 0.071 ad quinazolin-4-yl)-piperidin-4-yl ester 12 (6-Cyclobutoxy-pyridin-3-yl)-carbamic acid 1-(6,7-dimethoxy- 0.035 0.064 0.011 quinazolin4-yl)-pyrrolidin-3-yl ester .03.64.0 13 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic 0.037 0.855 0.089 acid (4-isopropyl-phenyl)-amide 14 (4-1sopropyl-phenyl)-carbamic acid 1-[6-(3-hydroxy-prop-1- 0.037 0.136 .004 y nyl)-quinazolin-4-yl]-pyrrolidin-3-yl ester 15 (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy- .042 .866 0.32 1 quinazolin-4-yl)-pyrrolidin-3-yl ester 187 WO 2006/135636 PCT/US2006/022142 FLT3 MV4-11 BaF3 No. Compound Name Kinase ELISA (uM) u) (uM) 16 1-(4-lsopropyl-phenyl)-3-(1-quinazolin-4-yl-pyrrolidin-3-yl)- 0.045 .278 .242 urea 17 (4-Isopropyl-phenyl)-carbamic acid 1-[6-(3-diethylamino- .063 .122 .163 prop-1 -ynyl)-quinazolin-4-yl]-pyrrolidin-3-yl ester 0.063 0.122 0.163 18 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-ylmethyl]-3- 0.066 1.3 0.049 (4-isopropyl-phenyl)-urea 19 1 -[1 -(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4- .068 1.38 .21 1 isopropyl-phenyl)-l -methyl-urea .0 13_ . 20 (4-Isopropyl-phenyl)-carbamic acid 1-(6-iodo-quinazolin-4- .096 .262 .043 yl)-pyrrolidin-3-yl ester 21 N-[i1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-2-(4- .15 .078 .063 isopropyl-phenyl)-acetamide 0.15 0.078 0.063 22 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-.17 1.7 .082 quinazolin-4-yl)-piperidin-4-ylmethyl ester 0.17 1.7 0.082 23 1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic .185 1.98 .1757 23 acid (4-isopropoxy-phenyl)-amide 0.185 1.98 0.1757 24 (4-Isopropyl-phenyl)-carbamic acid 1-quinazolin-4-yl-.29 .22 pyrrolidin-3-yl ester 0.29 .22 nd 25 1-[1-(6,7-Dimethoxy-quinazolin-4-yl)-azetidin-3-ylmethyl]-3- 0.408 >10 d (4-isopropoxy-phenyl)-urea 0 8 >d 26 1-[1 -(3-Cyano-6,7-dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl]-3- 0.433 1.9 0.331 (4-isopropyl-phenyl)-urea 27 1-(4-isopropyl-phenyl)-3-(1-quinolin-4-yl-pyrrolidin-3-yl)-urea 0.457 5.3 nd 28 1-[1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-3-yl]-3-(4- .51 1.5 1.9 isopropyl-phenyl)-urea .5 15 29 -[1 -(3-Cyano-6,7-dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl]-3- 0.531 1.7 3.1 29 (4-isopropoxy-phenyl)-urea.531 1.7 3.1 30 1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-4-carboxylic .563 2.31 acid (3-isopropoxy-phenyl)-amide .63 31 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy- 0.67 1.7 1.1 quinazolin-4-yl)-piperidin-3-yl ester 32 (4-Isopropoxy-phenyl)-carbamic acid 1-(3-cyano-6,7- .868 1.4 1.2 dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl ester 08 14 1 33 (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy- 1 .343 .559 quinazolin-4-yl)-piperidin-2-ylmethyl ester 1 0.343 .559 34 (4-isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl-pyrrolidin- 1.05 6.4 ad 3-yl ester 35 N-[1 -(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-2-(4- 1.3 1.9 >3 isopropyl-phenyl)-acetamide .... .. -- 36 1-[--(6,7-Die-thoxy-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4- 1.68 3.19 1.3 isopropoxy-phenyl)-1l-methyl-urea .6_. 1 37 (4-Isopropyl-phenyl)-carbamic acid 1-(3-cyano-6,7- 2.135 1.5 1.1 dimethoxy-quinolin-4-yl)-pyrrolidin-3-yl ester 38 1-(4-lsopropoxy-phenyl)-3-(1-quinolin-4-yl-pyrrolidin-3-yl)- 3.15 >3 d urea 188 WO 2006/135636 PCT/US2006/022142 FLT3 MV4-11 BaF3 No. Compound Name Kinase (U) ELISA __ __ _ ______________________________ (UM) (M) (UM) 39 (4-Isopropoxy-pheny!)-carbamic acid I1-quinolin-4-yI- 7.14 >10 nd pyrroiidin-3-yI ester ____ 40 (4-isopropoxy-phenyl)-carbamic acid 1 -(3-cyano-6,7- >10 nd nd _____dimethoxy-quinolin-4-y)-piperidin-4-yI ester______________ 41 (4-isopropoxy-phenyl)-carbamic acid I1-quinolin-4-yi- nd >10 nd _____piperidin-4-yl ester 42 (4-isopropyi-phenyl)-carbamic acid 1 -(3-cyano-6,7- nd 2.1 3 dimethoxy-quinolin-4.yt)-piperidin-4-yI ester _________ 43 1 -[1 -(6,7-Dimethoxy-quinazolin-4-y)-pyrroidin-3-y]-3-(4- nd >5 nd morpholin-4-yl-phenyl)-urea 44 1 -(6-Cyclobutoxy-pyridin-3y)-3-1 -(6,7-dimethoxy- nd 1 nd Iquinazolin-4-yI)-pyrrolidin-3-yI)-urea_____ 45 1 -(6-Cyclopentyloxy-pyridin-3-y)-3-[1 -(6,7-dimethoxy- nd 1.1 nd quinazolin-4-yl)-pyrrolidin-3-yi]-urea 46 1 -[1 -(6,7-Dimethoxy-quinazolin-4-y)-pyrrolidin-3-yi]-3-(6- nd 3.5 nd pyrrolidin-1 -yl-pyridin-3-yi)-urea ____ 47 1 -[1 -(6,7-Dimethoxy-quinazolin-4-yi)-pyrrolidin-3-yq]-3-(4- nd 3.9 nd piperidin-1 -yI-phenyl)-urea_____ 48 1 -(4-Chloro-phenyl)-3-[1 -(6,7-dimethoxy-quinazolin-4-y)- tid 2.5 nd _____pyrrolidin-3-yII-urea 49 1-[1 -(6,7-Dimethoxy-quinazoin-4-yl)-pyrrolidin-3-y]-3-(4- nd nd nd _____pyrrolidin-1 -yI-phenyl)-urea 50 1 -(4-Cyclohexyl-phenyl)-3-[1 -(6,7-dimethoxy-quinazolin-4- nd 1.7 nd yi)-pyrrolidin-3-yI]-urea ____ 51 1 -[1 -(6,7-Dimethoxy-quinazoin-4-y)-pyrrolidin-3-y]-3-(4- nd 1.2 nd phenoxy-phenyl)-urea ____ 52 1 -[l -(6,7-Dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yi]-3-(4- nd 0.83 6.6 dim ethylam ino-phenyl)-urea 53 1 -(4-Cyclopentyloxy-phenyl)-3-[1 -(6,7-dimethoxy-quinazolin- nd 1.5 nd 4-yl)-pyrrolidin-3-yl]-urea ____ 54 (4-Cyclopentyloxy-phenyl)-carbamic acid 1 -(6,7-dimethoxy- nd 1.5 nd quinazolin-4-yI)-pyrroidin-3-yI ester 55 (4-Cyclopentyloxy-phenyl)-carbamic acid 1 -(6,7-dimethoxy- nd 0.56 0.42 quinazolin-4-yl)-piperidin-4-yl ester 56a (4-Cyclopentyloxy-phenyl)-carbamic acid 1 -(6,7-dimethoxy- nd 0.74 3 quinazolin-4-yI)-piperidin-4-ylmethyi ester_____ 57 (4-Cyclopentyloxy-phenyl)-carbamic acid 1 -(6,7-dimethoxy- nd 0.172 0.046 quinazolin-4-yi)-piperidin-3-yimethyI ester _________ 58 1 -1 -(6,7-Dimethoxy-quinazoin-4-y)-piperidin-4-ylj-3-(4- nd 0.007 0.180 _____isopropoxy-phenyl)-urea --- ____ 59 1 [1 -(6,7-Dirnethoxy-quinazolin-4-y)-piperidin-4-y]-3-(4- nd 0.410 0.043 morpholin-4-yI-phenyl)-urea 60 1 -1 -(6,7-Dimethoxy-quinazolin-4-y)-piperidin-4-yj-3-(4- nd 0.528 0.018 pyrrolidin-1 -yI-phenyl)-urea _____ ________ 61 1 -(4-Chloro-phenyl)-3-1 -(6,7-dimethoxy-quinazolin-4-y)- nd 9.4 nd _____piperidin-4-yiII-urea_____ _________ 189 WO 2006/135636 PCT/US2006/022142 FLT3 MV4-11 BaF3 No. Compound Name Kinase ELISA (uM) (M) (uM) 62 1-[1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4- nd 0.941 0.016 dimethylamino-phenyl)-urea 63 1-(4-Isopropyl-phenyl)-3-(1 -quinazolin-4-yl-piperidin-4-yl)- nd 0.502 0.020 urea 64 1-(4-Isopropyl-phenyl)-3-[1 -(6-methoxy-quinazolin-4-yl)- nd 0.016 0.011 piperidin-4-yl]-urea 65 1-(4-Isopropyl-phenyl)-3-[1 -(7-methoxy-quinazolin-4-yl)- nd 0.321 0.178 piperidin-4-yl]-urea 66 1-[1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(4- nd 0.001 0.001 isopropyl-phenyl)-urea 67 1-(4-Cyclopentyloxy-phenyl)-3-[1-(6,7-dimethoxy-quinazolin- nd 0.47 1.4 4-yl)-piperidin-4-yl]-urea 68 1-(1 -(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-3-(6- nd 0.134 0.016 pyrrolidin-1 -yl-pyridin-3-yl)-urea 69 1-[1 -(7-Fluoro-quinazolin-4-yl)-pyrrolidin-3-yl]-3-(4-isopropyl- nd 0.128 <0.001 phenyl)-urea 1-(4-Isopropyl-phenyl)-3-(1 -{7-[2-(2-oxo-pyrrolidin- 1-yl)- nd 0.021 0.080 70 ethoxy]-quinazolin-4-yl}-pyrrolidin-3-yl) urea 71 1-(4-Isopropyl-phenyl)-3-{1 -[7-(2-methoxy-ethoxy)- nd 0.001 0.001 quinazolin-4-yl]-pyrrolidin-3-yl}-urea 72 1-[1-(7-Fluoro-quinazolin-4-yl)-piperidin-4-yl]-3-(4-isopropyl- nd 0.245 0.03 phenyl)-urea 73 1-(4-Isopropyl-phenyl)-3-{1 -[7-(2-methoxy-ethoxy)- nd 0.208 0.109 quinazolin-4-yl]-piperidin-4-yl}-urea 74 1-(4-Isopropyl-phenyl)-3-(1-{7-[2-(2-oxo-pyrrolidin-1 -yl)- nd 0.177 0.004 ethoxy]-quinazolin-4-yl}-piperidin-4-yl)-urea 75 1-(4-Isopropyl-phenyl)-3-(1-{7-[3-(4-methyl-piperazin-1 -yl)- nd 0.001 0.001 propoxy]-quinazolin-4-yl}-piperidin-4-yl)-urea * Except where indicated, compound names were derived using nomenclature rules well known to those skilled in the art, by either standard IUPAC nomenclature references, such as Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F and 5 H, (Pergamon Press, Oxford, 1979, Copyright 1979 IUPAC) and A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations 1993), (Blackwell Scientific Publications, 1993, Copyright 1993 IUPAC); or commercially available software packag-es-sch as Ai-foi-6m (brand of nomenclature software provided in the ChemDraw Ultra® office suite marketed by CambridgeSoft.com); and ACD/Index 10 Name M (brand of commercial nomenclature software marketed by Advanced Chemistry Development, Inc., Toronto, Ontario). 190 WO 2006/135636 PCT/US2006/022142 Other FLT3 Inhibitors Other FLT3 kinase inhibitors which can be employed in accordance with the present include: AG1295 and AG1296; Lestaurtinib (also known as CEP 701, formerly KT 5 5555, Kyowa Hakko, licensed to Cephalon); CEP-5214 and CEP-7055 (Cephalon); CHIR-258 (Chiron Corp.); EB-10 and IMC-EB10 (ImClone Systems Inc.); GTP 14564 (Merk Biosciences UK). Midostaurin (also known as PKC 412 Novartis AG); MLN 608 (Millennium USA); MLN-518 (formerly CT53518, COR Therapeutics Inc., licensed to Millennium Pharmaceuticals Inc.); MLN-608 (Millennium 10 Pharmaceuticals Inc.); SU-11248 (Pfizer USA); SU-11657 (Pfizer USA); SU-5416 and SU 5614; THRX-165724 (Theravance Inc.); AMI-10706 (Theravance Inc.); VX 528 and VX-680 (Vertex Pharmaceuticals USA, licensed to Novartis (Switzerland), Merck & Co USA); and XL 999 (Exelixis USA). 15 FORMULATION The FLT3 kinase inhibitors and the farnesyl transferase inhibitors of the present invention can be prepared and formulated by methods known in the art, and as 20 described herein. In addition to the preparation and formulations described herein, the farnesyltransferase inhibitors of the present invention can be prepared and formulated into pharmaceutical compositions by methods described in the art, such as the publications cited herein. For example, for the farnesyltransferase inhibitors of formulae (I), (II) and (III) suitable examples can be found in WO-97/21701. The 25 farnesyltransferase inhibitors of formulae (IV), (V), and (VI) can be prepared and formulated using methods described in WO 97/16443, farnesyltransferase inhibitors of formulae (VII) and (VIII) according to methods described in WO 98/40383 and WO 98/49157 and farnesyltransferase inhibitors of formula (IX) according to methods described in WO 00/39082 respectively. Tipifarnib (ZarnestraTM, also known as 30 R1 15777) and its less active enantiomer can be synthesized by-methods-described in WO 97/21701. Tipifarnib is expected to be available commercially as ZARNESTRATM in the near future, and is currently available upon request (by contract) from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Titusville, NJ). 191 WO 2006/135636 PCT/US2006/022142 Where separate pharmaceutical compositions are utilized, the FLT3 kinase inhibitor or farnesyl transferase inhibitor, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding 5 techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. A unitary pharmaceutical composition having both the FLT3 kinase inhibitor and farnesyl transferase inhibitor as active ingredients can be similarly prepared. 10 In preparing either of the individual compositions, or the unitary composition, in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for 15 example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar 20 coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In preparation for slow release, a slow release carrier, 25 typically a polymeric carrier, and a compound of the present invention are first dissolved or dispersed in an organic solvent. The obtained organic solution is then added into an aqueous solution to obtain an oil-in-water-type emulsion. Preferably, the aqueous solution includes surface-active agent(s). Subsequently, the organic solvent is evaporated from.the oil-in-water-type-emulsion-to-obtain a-colloidal 30 suspension of particles containing the slow release carrier and the compound of the present invention. 192 WO 2006/135636 PCT/US2006/022142 The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, 5 capsule, powder, injection, suppository, teaspoonful and the like, from about 0.01 mg to 200 mg/kg of body weight per day. Preferably, the range is from about 0.03 to about 100 mg/kg of body weight per day, most preferably, from about 0.05 to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 5 times per day. The dosages, however, may be varied depending upon the 10 requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, 15 powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble 20 salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other 25 pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughoutthe-composition-so that-the composition-may be readily subdivided 30 into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or 193 WO 2006/135636 PCT/US2006/022142 otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist 5 disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, acetyl alcohol and cellulose acetate. 10 The liquid forms in which the FLT3 kinase inhibitor and the farnesyl transferase inhibitor individually (or both in the case of a unitary composition) may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as 15 elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrolidone or gelatin. The liquid forms in suitably flavored suspending or dispersing agents may also include the synthetic and natural gums, for example, tragacanth, 20 acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. Advantageously, the FLT3 kinase inhibitor and the farnesyl transferase inhibitor may 25 be administered in a single daily dose (individually or in a unitary composition), or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention (individually or in a unitary composition) can be administered in intranasal form via topical use of suitable intranasal vehicles,_or viatransdermal-skin-patches-well- known-to those of ordinary 30 skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. 194 WO 2006/135636 PCT/US2006/022142 For instance, for oral administration in the form of a tablet or capsule, the active drug component (the FLT3 kinase inhibitor and the farnesyl transferase inhibitor individually, or together in the case of a unitary composition) can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, 5 water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, 10 sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The daily dosage of the products of the present invention may be varied over a wide range from 1 to 5000 mg per adult human per day. For oral administration, the 15 compositions are preferably provided in the form of tablets containing, 0.01,0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 200 mg/kg of body weight per day. Particularly, the 20 range is from about 0.03 to about 15 mg/kg of body weight per day, and more particularly, from about 0.05 to about 10 mg/kg of body weight per day. The FLT3 kinase inhibitor and the farnesyl transferase inhibitor individually, or together in the case of a unitary composition, may be administered on a regimen up to four or more times per day, preferably of 1 to 2 times per day. 25 Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated- with-the-particular-patient being 30 treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages. 195 WO 2006/135636 PCT/US2006/022142 The FLT3 kinase inhibitor and the farnesyl transferase inhibitor of the present invention can also be administered (individually or in a unitary composition) in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a 5 variety of lipids, including but not limited to amnphipathic lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, phophatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes, and stearylamine, neutral lipids such as 10 triglycerides, and combinations thereof. They may either contain cholesterol or may be cholesterol-free. The FLT3 kinase inhibitor and the farnesyl transferase inhibitor of the present invention can also be administered (individually or in a unitary composition) locally. 15 Any delivery device, such as intravascular drug delivery catheters, wires, pharmacological stents and endoluminal paving, may be utilized. The delivery system for such a device may comprise a local infusion catheter that delivers the compound at a rate controlled by the administor. 20 The present invention provides a drug delivery device comprising an intraluminal medical device, preferably a stent, and a therapeutic dosage of the FLT3 kinase inhibitor and the farnesyl transferase inhibitor of the invention. Alternatively, the present invention provides for individual administration of a therapeutic dosage of one or both of the FLT3 kinase inhibitor and the farnesyl transferase inhibitor of the 25 invention by means of a drug delivery device comprising an intraluminal medical device, preferably a stent The term "stent" refers to any device capable of being delivered by a catheter. A stent is routinely used to prevent vascular closure due to physical anomalies such as 30 unwanted inward growth of vascular tissue due to surgical trauma. It often has a tubular, expanding lattice-type structure appropriate to be left inside the lumen of a duct to relieve an obstruction. The stent has a lumen wall-contacting surface and a lumen-exposed surface. The lumen-wall contacting surface is the outside surface of 196 WO 2006/135636 PCT/US2006/022142 the tube and the lumen-exposed surface is the inner surface of the tube. The stent can be polymeric, metallic or polymeric and metallic, and it can optionally be biodegradable. 5 The FLT3 kinase inhibitor and farnesyl transferase inhibitor of the present invention (individually or in a unitary composition) can be incorporated into or affixed to the stent in a number of ways and in utilizing any number of biocompatible materials. In one exemplary embodiment, the compound is directly incorporated into a polymeric matrix, such as the polymer polypyrrole, and subsequently coated onto the outer 10 surface of the stent. The compound elutes from the matrix by diffusion through the polymer. Stents and methods for coating drugs on stents are discussed in detail in the art. In another exemplary embodiment, the stent is first coated with as a base layer comprising a solution of the compound, ethylene-co-vinylacetate, and polybutylmethacrylate. Then, the stent is further coated with an outer layer 15 comprising only polybutylmethacrylate. The outlayer acts as a diffusion barrier to prevent the compound from eluting too quickly and entering the surrounding tissues. The thickness of the outer layer or topcoat determines the rate at which the compound elutes from the matrix. Stents and methods for coating are discussed in detail in WIPO publication WO9632907, U.S. Publication No. 2002/0016625 and references 20 disclosed therein. To better understand and illustrate the invention and its exemplary embodiments and advantages, reference is made to the following experimental section. 25 EXPERIMENTALS Inhibition of AML cell growth with the combination of an FTI and a FLT3 inhibitor 30 was tested. Two FTIs, Tipifarnib and FTI Compound 176 ("FTI-176), and eight novel FLT3 inhibitors: Compounds A, B, C, D, E, F G and H were used to inhibit the growth of FLT3-dependent cell types in vitro (see Figure 5 depicting the test compounds). 197 WO 2006/135636 PCT/US2006/022142 The cell lines that were tested included those that are dependent on FLT3ITD mutant activity for growth (MV4-11 and Baf3-FLT3ITD), FLT3wt activity for growth (Baf3FLT3) and those that grow independent of FLT3 activity (THP-1). MV4-11 5 (ATCC Number: CRL-9591) cells are derived from a patient with childhood acute myelomonocytic leukemia with an 1 1q23 translocation resulting in a MLL gene rearrangement and containing an FLT3-ITD mutation (AML subtype M4) (see Drexler HG. The Leukemia-Lymphoma Cell Line Factsbook. Academic Pres: San Diego, CA, 2000 and Quentmeier H, Reinhardt J, Zaborski M, Drexler HG. FLT3 10 mutations in acute myeloid leukemia cell lines. Leukemia. 2003 Jan;17:120-124.). Baf3-FLT3 and Baf3-FLT31TD cell lines were obtained from Dr. Michael Henrich and the Oregon Health Sciences University. The Baf3 FLT3 cell lines were created by stable transfection of parental Baf3 cells (a murine B cell lymphoma line dependent on the cytokine IL-3 for growth) with either wild-type FLT3 or FLT3 15 containing the ITD insertion in the juxatamembrane domain of the receptor resulting in its constitutive activation. Cells were selected for their ability to grow in the absence of IL-3 and in either the presence of FLT3 ligand (Baf3-FLT3) or independent of any growth factor (Baf3-ITD). THP-1 (ATCC Number: TIB-202) cells were isolated from a childhood AML patient with an N-Ras mutation and no 20 FLT3 abnormality. Although the cells express a functional FLT3 receptor, THP-1 cells are not dependent on FLT3 activity for viability and growth (data not shown). Dose responses for the individual compounds alone were determined for each cell line using a standard 72-hour cell proliferation assay (see Figures 6.1 - 6.8). The 25 standard chemotherapeutic agent Cytarabine was used as a control cytotoxic agent in all experiments. The FTI Tipifarnib has a potency range of high nanomolar to high picomolar range depending on the cell type. The FLT3 inhibitors, Compounds A, B,C,D, E, F G and H, individually have good potency (sub-micromolar) for the inhibition of FLT3 driven proliferation comparedd to the-first-line cytotoxic agent 30 Cytarabine and Tipifarnib) in cells that depend on FLT3 for growth. Each of these chemically distinct compounds alone has potential for the treatment of disorders related to FLT3, such as FLT3 positive AML. Cytarabine inhibition of proliferation is comparable (1-2pM) to previous reports of its in vitro activity in MV4-11 cells 198 WO 2006/135636 PCT/US2006/022142 (Levis, M., et al. (2004) "In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects." Blood. 104(4):1145-50). The FLT3 inhibitors tested had no effect on THP-1 proliferation. The IC 50 calculation for each compound in each cell line was 5 used in subsequent combination experiments to calculate synergistic effects of compound combinations on cell proliferation. (See Figures 10.1 - 10.8 and Tables 1 3, hereafter.) The effect of a single (sub- IC 50 ) dose of the FLT3 inhibitor Compound A on 10 Tipifarnibpotency was then examined. Each cell line was simultaneously treated with one dose of the FLT3 inhibitor Compound A and varying doses of Tipifarnib and the proliferation of the cells was evaluated in the standard 72-hour cell proliferation protocol. The IC 50 for Tipifarnib was then calculated according to the procedure described in the Biological Activity section hereafter (see Figures 7a-c depicting 15 results for FLT3 inhibitor Compound A and Tipifarnib combination.) The cell lines that were tested included those that are dependent on FLT3ITD mutant activity for growth (MV4-11 and Baf3-FLT3ITD), FLT3wt activity for growth (Baf3FLT3) and those that grow independent of FLT3 activity (THP-1). 20 The FLT3 inhibitor Compound A significantly increased the potency of the FTI Tipifarnib for the inhibition of AML (MV4-11) and FLT3 dependent (Baf3-ITD and Baf3-FLT3) cell proliferation. With a single sub-IC 50 so dose of FLT3 inhibitor Compound A in (a) MV4-11 (50nM); (b) Baf3-ITD (50nM) and (c) Baf3-FLT3 (100inM) cells, Tipifarnib increased in potency by more than 3-fold in each cell line 25 tested. This is indicative of significant synergy. Next, single dose combinations of the FTI Tipifarnib and the FLT3 inhbitor Compound A were evaluated in the MV4-11, Baf3-ITD and Baf3-FLT3 cell lines. This single dosecombination scenario-more closely represents dosing strategies for 30 chemotherapeutic combinations that are used in the clinic. With this method cells are simultaneously treated with a single sub- IC 50 so of dose of each compound or a combination of compounds and inhibition of proliferation was monitored. Using this method it is observed that combinations of a sub- IC 50 so dose of the FTI Tipifarnib and 199 WO 2006/135636 PCT/US2006/022142 the FLT3 inhibitor Compound A are beyond additive in inhibiting the growth of the AML cell line MV4-11 and other FLT3-dependent cells (see Figures 8a-d). This synergistic effect with Tipifarnib is not observed in cells that do not depend on FLT3 for proliferation (THP-1). This synergistic effect was also observed for combinations 5 of FLT3 inhibitor Compound A and Cytarabine. Additionally, single dose combinations of a FLT3 inhibitor and a FTI were examined to determine if this activity was compound specific or mechanism based. A single sub- IC 50 of dose of either FLT3 inhibitor Compound B or D with Tipifarnib was 10 tested for its inhibition of MV4-11 proliferation. It is observed, similar to combinations of Tipifarnib and FLT3 inhibitor Compound A, that the combinations of either FLT3 inhibitor Compound B or D with Tipifarnib inhibits the proliferation of FLT3-dependent MV4-11 cells with greater that additive efficacy. This suggests that the combination of any FLT3 inhibitor and FTI will synergistically inhibit the 15 proliferation of FLT3-dependent AML cells. This observation is novel and non obvious to those skilled in the art. Synergy was also observed with the combination of either FLT3 inhihbitor Compound B or D and cytarabine. To statistically evaluate the synergy of a FLT3 inhibitor and an FTI in FLT3 20 dependent cell lines, dosing combinations were evaluated by the method of Chou and Talalay. See Chou TC, Talalay P. (1984) "Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors." Adv Enzyme Regul. 22:27-55. Using this method inhibitors are added simultaneously to cells in a ratio of the IC 50 dose of each compound alone. The data is collected and 25 subject to isobolar analysis of fixed ratio dose combinations as described by Chou and Talalay. This analysis is used to generate a combination index or CI. The CI value of 1 corresponds to compounds that behave additively; CI values < 0.9 are considered synergistic and CI values of >1.1 are considered antagonistic. Using this method, multiple FTI and FLT3 combinations were evaluated. For-each experimental 30 combination ICs 5 os were calculated for each individual compound (see Figures 6.1-6.8) in each of the FLT3 dependent cell lines and then fixed ratio dosing (at dose ranges including 9,3,1,1/3, 1/9 x the individual compound IC 50 ) was performed in the standard cell proliferation assay. Figures 10.1 - 10.8 summarizes the raw data from 200 WO 2006/135636 PCT/US2006/022142 isobolar analysis fixed ratio dosing according to the method of Chou and Talalay, obtained using Calcusyn software (Biosoft). Using the isobologram, synergy can be graphically represented. Data points for combinations that are additive lie along the isobolar line at a given dose affect (CI= 1). Data points for combinations that are 5 synergistic fall to the left, or under, the isobolar line for a given dose effect (CI < 0.9). Data points for combinations that are antagonistic fall to the right, or over, the isobolar line for a given dose effect (CI > 1.1). Figure 10.1a-c summarizes the isobolar analysis for the combination of FLT3 inhibitor Compound A and Tipifarnib in MV4-11, Baf3-ITD and Baf3-wtFLT3. From the isobolar analysis, synergy was 10 observed at all experimentally determined data points including the combination doses that resulted in a 50% inhibition of cell proliferation (ED50), a 75% inhibition of cell proliferation (ED75) and a 90% inhibition of cell proliferation (ED90). Each of these points falls significantly to the left of the isobolar (or additive) line, indicating significant synergy. The combination of FLT3 inhibitor Compound A and 15 Tipifarnib resulted in significant synergy for proliferation inhibition in each FLT3 dependent cell lines tested. The combination indecies for the isobolograms depicted in Figures 10.1a-c are found in Tables 1-3 hereafter. Additionally, Figures 10.2a-b summarizes the isobolar analysis with the combination 20 of a chemically distinct FLT3 inhibitor, FLT3 inhibitor Compound B and Tipifarnib. Similar to the FLT3 inhibitor Compound A and Tipifarnib combination, the FLT3 inhibitor Compound H and Tipifarnib combination was synergistic for inhibiting cellular proliferation at all doses tested and in all FLT3-dependent cell lines tested. The combination indecies for the isobolargrams depicted in Figures 5.2a-c are found 25 in Tables 1-3 hereafter. Futhermore, Figures 5.3a-c summarizes the isobolar analysis of a combination of Tipifarnib and another chemically distinct FLT3 inhibitor (FLT3 inhibitor Compound E). As with the other combinations tested, the combination of FLT3 inhibitor compound E and Tipifarnib synergistically inhibited FLT3-dependent proliferation in threedifferent celllines at-all doses tested; -The combination indecies 30 for the isobolargrams depicted in Figures 5.3a-c are found in Tables 1-3 hereafter. To further expand the combination studies, each of the FLT3 inhibitors shown to demonstrate synergy with Tipifarnib were also tested in combination with another 201 WO 2006/135636 PCT/US2006/022142 farnesyl transferase inhibitor, FTI-176. Tables 1-3 summarize the results of all the combinations tested in the three FLT3-dependent cell lines described above. The combination indecies for each combination are contained within Tables 1-3. 5 TABLE 1 Table 1: The combination of a FLT3 inhibitor and an FTI (all combinations tested) synergistically inhibits the proliferation of MV4-11 AML cells as measured by the Combination Index (CI). Combinations were performed at a fixed ratio of the 10 individual compound ICs 5 os for proliferation as summarized in Biological Activity Measurments section hereafter. IC 50 and CI values were calculated by the method of Chou and Talalay using Calcusyn software (Biosoft). CI and IC 50 values are an average of three independent experiments with three replicates per data point. FTI FLT3 inhibitor IC50 MV4-11 cells CI - ED50 CI - ED75 CI - ED90 IC50 n (nM) (nM) Tipifarnib 15.41 FTI-176 17.73 FLT3 inhibitor Compound A 92.53 FLT3 inhibitor Compound B 31.3 FLT3 inhibitor Compound C 18.1 FLT3 inhibitor Compound D 13.8 FLT3 inhibitor Compound H 166.93 FLT3 inhibitor Compound E 32.81 Tipifarnib + Tipifarnib + 0.58 0.52 0.46 3.96 28.12 FLT3 inhibitor Compound A Tipifarnib + Tin ibo 0.79 0.66 0.60 4.48 9.86 FLT3 inhibitor Compound B Tipifarnib + 3.65 0.78 0.62 0.55 . 65.... .. . ........ 3.86... .. FLT3 inhibitor Compound C - Tipifarnib + 0.67 0.62 0.59 4.19 3.75 FLT3 inhibitor Compound D Tipifarnib + Tipfani +0.56 0.51 0.48 4.39 64.81 FLT3 inhibitor Compound H 056 0.51 048 439 6481 202 WO 2006/135636 PCT/US2006/022142 FTI FI FLT3 inhibitor IC50 MV4-11 cells CI - ED50 CI - ED75 CI - ED90 IC50 FLT3 inhibitor 150 (nM) (nM) Tipifarnib + FLT3 inhibitor Compound E 0.67 0.62 0.59 4.19 1.75 Tipifarnib + FLT3 inhibitor Compound F 0.69 0.59 0.55 4.23 11.67 Tipifarnib + FLT3 inhibitor Compound G 0.75 0.61 0.68 4.84 145.15 FTI 176 + FTI 176+ 0.62 0.60 0.59 4.63 30.12 FLT3 inhibitor Compound A FTI 176 + FLT3 inhibitor Compound H 0.66 0.63 0.61 5.81 50.94 FTI 176 + FLT3 inhibitor Compound E 0.68 0.64 0.61 5.69 9.37 FTI 176 + FLT3 inhibitor Compound D 0.71 0.63 0.60 4.72 5.48 TABLE 2 Table 2: The combination of a FLT3 inhibitor and an FTI (all combinations tested) 5 synergistically inhibits the proliferation of Baf3-FLT3 cells stimulated with 100ng/ml FLT ligand as measured by the Combination Index (CI). Combinations were performed at a fixed ratio of the individual compound IC50s for proliferation as summarized in Biological Activity Measurments section hereafter. IC50 and CI values were calculated by the method of Chou and Talalay using Calcusyn software 10 (Biosoft). CI and IC 50 values are an average of three independent experiments with three replicates per data point. FTI FLT3 inhibitor Baf3-FLT3 CI - ED50 CI - ED75 CI - ED90 FTI FLT3 inhibitor IC50 (nM) IC50 (nM) Tipifarnib 1.85 FTI-176 1.35 FLT3 inhibitor Compound A 169.77 FLT3 inhibitor Compound B 173.1 FLT3 inhibitor Compound C 91.3 FLT3 inhibitor Compound D 39.90 203 WO 2006/135636 PCT/US2006/022142 FTI FLT3 inhibitor Baf3-FLT3 CI - ED50 CI - ED75 CI - ED90 FTI FLT3 inhibitor IC50 (nM) IC50 (nM) FLT3 inhibitor Compound H 451.37 FLT3 inhibitor Compound E 29.40 Tipifarnib + Tin ibo C 0.45 0.40 0.37 0.333 48.24 FLT3 inhibitor Compound A Tipifarnib + Tinhibi 0.78 0.67 0.62 0.431 23.26 FLT3 inhibitor Compound B Tipifarnib + Tipifarnib + 0.81 0.71 0.65 0.442 63.41 FLT3 inhibitor Compound C Tipifarnib + Tin ibo C 0.60 0.53 0.49 0.360 12.31 FLT3 inhibitor Compound D Tipifarnib + Tipifarnib + 0.38 0.36 0.35 0.277 125.28 FLT3 inhibitor Compound H Tipifarnib + Tin ibo 0.42 0.39 0.38 0.360 23.26 FLT3 inhibitor Compound E FTI 176 + T t C u 0.55 0.40 0.32 0.374 56.33 FLT3 inhibitor Compound A FTI 176 + F 176 + 0.60 0.56 0.48 0.380 11.61 FLT3 inhibitor Compound D FTI 176 + T t C u 0.44 0.34 0.27 0.290 145.11 FLT3 inhibitor Compound H FTI 176 + 3 t C u 0.49 0.39 0.33 0.391 25.16 FLT3 inhibitor Compound E TABLE 3 Table 3: The combination of a FLT3 inhibitor and an FTI (all combinations tested) 5 synergistically inhibits the proliferation of Baf3-ITD cells as measured by the Combination Index (CI). Combinations were performed at a fixed ratio of the individual compound IC50s for proliferation as summarized in Biological Activity Measurments section hereafter. IC50 and CI values were calculated by the method of Chou and Talalayn sing-Calcusyn-software (-Biosoft). CI-and-IC 5 o values are an 10 average of three independent experiments with three replicates per data point. 204 WO 2006/135636 PCT/US2006/022142 Baf3-FLT3 cells C - ED50 C - ED75 C - ED90 FTI FLT3 inhibitor Ba3-FLT3 cells CI - ED5C - ED75 C - ED9 IC50 (nM) IC50 (nM) Tipifarnib 547.87 FTI-176 667.86 FLT3 inhibitor Compound A 76.12 FLT3 inhibitor Compound D 14.56 FLT3 inhibitor Compound H 200.17 FLT3 inhibitor Compound E 29.40 Tipifarnib + FLT3 inhibitor 0.72 0.63 0.62 146.83 27.19 Compound A Tipifarnib + FLT3 inhibitor 0.68 0.65 0.63 165.60 4.87 Compound D Tipifarnib + FLT3 inhibitor 0.92 0.87 0.84 172.80 71.49 Compound H Tipifarnib + FLT3 inhibitor 0.82 0.78 0.75 189.10 11.85 Compound E FTI 176 + FLT3 inhibitor 0.74 0.62 051 224.36 25.37 Compound A FTI 176 + FLT3 inhibitor 0.75 0.69 0.63 231.68 4.12 Compound D FTI 176 + FLT3 inhibitor 0.62 0.60 0.58 183.38 68.54 Compound H FTI 176 + FLT3 inhibitor 0.51 0.50 0.50 220.80 8.91 Compound E Synergy of combination dosing is observed with all FTI and FLT3 combinations tested in all FLT3 dependent cell lines used. The combination of an FTI and FLT3 inhibitor reduces the individuaLcompounds antiproliferative effect by an average of 3 5 4fold. It can be concluded that the synergy observed for combinations of a FLT3 inhibitor and an FTI is a mechanism based phenomena and not related to the specific chemical structures of individual FTIs or FLT3 inhibitors. Accordingly, synergistic 205 WO 2006/135636 PCT/US2006/022142 growth inhibition would be observed with any combination of a FLT3 inhibitor and Tipifarnib or any other FTL The ultimate goal of treatment for FLT3 related disorders is to kill the disease 5 causative cells and to cause regression of disease. To examine if the FTIFLT3 inhibitor combination is synergistic for cell death of FLT3 dependent disease causative cells, particularly AML, ALL and MDS cells, the combination of Tipifarnib and the FLT3 inhibitor Compound A was tested for its ability to induce an increase in fluorescent labeled Annexin V staining in MV4-11 cells. Annexin V binding to 10 phosphotidyl serine that has translocated from the inner leaflet of the plasma membrane to the outer leaflet of the plasma membrane and is a well established way to measure apoptosis of cells. See van Engeland M., L.J. Nieland ,et al. (1998) "Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure." Cytometry. 31(1):1-9. 15 Tipifarnib and FLT3 inhibitor Compound A were incubated with MV4-11 cells alone or in a fixed ratio (4:1 based on the calculated ECso for each agent alone) for 48 hours in standard cell culture conditions. After the compound incubations, treated cells were harvested and stained with Annexin V-PE and 7-AAD using the Guava Nexin 20 apoptosis kit according to the protocol in the Biological Activity Measurements section hereafter. Annexin V staining peaks at 60% because cells late in apoptosis begin to fall apart and are considered debris. However, EC 5 0s can be calculated from this data because of its consistent sigmoidal kinetics. From the data summarized in Figure 11a, it is concluded that the combination of Tipifarnib and FLT3 inhibitor 25 Compound A is significantly more potent than either agent alone for inducing apoptosis of MV4-11 cells. The EC 50 for the induction of annexin V staining shifted more than 4-fold for the FLT3 inhibitor FLT3 inhibitor Compound A. The ECs 50 for induction of annexin V staining shifted by more than eight-fold for the FTI Tipifarnib. Statistical analysis using the above described method of Chou and Talalay was also 30- performied- to deteieiiiie the synergy- of the combination. Figure lib depictes the isobolar analysis of the Tipifarnib and FLT3 inhibitor Compound A combination in inducing annexin V staining. All data points lie significantly to the left of the isobolar line. The CI values for the combination are listed in the table in Figure 11c. The 206 WO 2006/135636 PCT/US2006/022142 synergy that was observed for annexin V staining (and induction of apoptosis) were more significant than the synergies that were observed for the FLT3 inhibitor and FTI combinations for proliferation. The magnitude of the synergistic induction of apoptosis of MV4-11 cells by the combination of an FTI and a FLT3 inhibitor could 5 not be predicted by those skilled in the art. Thus, based on the data from proliferation, any combination of a FLT3 inhibitor and an FTI would also be synergistic for inducing apoptosis of FLT3 dependent cells (i.e. causative cells for FLT3 disorders, particularly AML, ALL and MDS). 10 To confirm that the combination of a FLT3 inhibitor and an FTI synergistically activates apoptosis of FLT3 dependent cells, the combination of several FLT3 inhibitors and the FTI Tipifarnib was tested for its ability to induce the activity of caspase 3/7 in MV4-11 cells. Caspase activation, a critical step in the final execution of the apoptotic cellular death process, can be induced by a variety of cellular stimuli 15 including growth factor withdrawal or growth factor receptor inhibition See Hengartner, MO. (2000) "The biochemistry of apoptosis." Nature 407:770-76 and Nunez G, Benedict MA, Hu Y, Inohara N. (1998) "Caspases: the proteases of the apoptotic pathway." Oncogene 17:3237-45. Cellular caspase activation can be monitored using a synthetic caspase 3/7 substrate that is cleaved to release a substrate 20 for the enzyme luciferase, that may convert the substrate to a luminescent product. See Lovborg H, Gullbo J, Larsson R. (2005) "Screening for apoptosis-classical and emerging techniques." Anticancer Drugs 16:593-9. Caspase activation was monitored using the Caspase Glo technology from Promega (Madison, WI) according to the protocol in the Biological Activity Measurement section hereafter. 25 Individual EC 50 determinations were done to establish dose ratios for combination analysis of synergy. Figure 12a-d summarizes the ECs 0 determinations of each individual agent. For combination experiments, Tipifarnib and FLT3 inhibitor CompoundsB, C and Dwere incubatedwithlMV4-1- cells-in a fixed-ratio-(based on 30 the calculated EC 50 for each agent alone) at various doses (ranges including 9,3,1,1/3, 1/9 x the individual compound ECso) for 24 hours in standard cell culture conditions. After 24 hours the caspase 3/7 activity was measured according to the manufacture's instructions and detailed in the Biological Activity Measurement section hereafter. 207 WO 2006/135636 PCT/US2006/022142 Figure 13.1 -13.3 summarizes the synergy of caspase activation (by the method previously described method of Chou and Talalay) that was observed with the Tipifarnib and FLT3 inhibitor Compounds B, C and D combinations in MV4-11 cells. Synergy was observed at all doses tested and in all combinations tested. The synergy 5 that was observed for caspase activation (and induction of apoptosis) was even more significant than the synergies that were observed for the FLT3 inhibitor and FTI combinations for proliferation in MV4-11 cells. The magnitude of the synergistic induction of apoptosis of MV4-11 cells by the combination of an FTI and a FLT3 inhibitor could not be predicted by those skilled in the art. Thus, based on the data 10 from proliferation, any combination of a FLT3 Inhibitor and an FTI would also be synergistic for inducing apoptosis of FLT3 dependent cells (i.e. causative cells for FLT3 disorders, particularly AML, ALL and MDS). It is well established that phosphorylation of the FLT3 receptor and downstream 15 kinases such as MAP kinase are required for proliferative effects of FLT3 receptor. See Scheijen, B. and J. D. Griffin (2002) "Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease." Oncogene 21(21): 3314-33. We postulate that the molecular mechanism of the synergy observed with a FLT3 inhibitor and an FTI is related to the compound induced decrease of FLT3 receptor signaling required 20 for AML cell proliferation and survival. To test this we looked at phosphorylation state of both the FLT3-ITD receptor and a downstream target of FLT3 receptor activity, MAP kinase (erkl/2) phosphorylation in MV4-11 cells, using commercially available reagents according to the protocol detailed in the Biological Activity Measurements section hereafter. MV4-11 cells were treated with indicated 25 concentrations of FLT3 inhibitor Compoud A alone or in combination with Tipifarnib for 48 hours under standard cell growth conditions. For analysis of FLT3 phosphorylation, cells were harvested and FLT3 was immunoprecipitated and separated by SDS-PAGE. For analysis of MAP kinase (erkl/2) phosphorylation, cells wereharvested, subjected tolysis, separated-bySDS-Page and transferred-to - 30 nitrocellulose for immunoblot analysis. For quantitative analysis of FLT3 phosphorylation, immunoblots were probed with phosphotyrosine antibody and the phophoFLT3 signal was quantified using Molecular Dynamics Typhoon Image Analysis. The immunoblots were then stripped and reprobed to quantify the total 208 WO 2006/135636 PCT/US2006/022142 FLT3 protein signal. This ratio of phosphorylation to total protein signal was used to calculate the approximate IC 50 of the compound dose responses. For quantitative analysis of MAP kinase (ERK1/2) phosphorylation, immunoblots were probed with a phosphospecific ERK1/2 antibody and the phophoERK1/2 signal was quantified 5 using Molecular Dynamics Typhoon Image Analysis. The immunoblots were then stripped and reprobed to quantify the total ERK1/2 protein signal. This ratio of phosphorylation to total protein signal was used to calculate the approximate ICs 50 of the compound dose responses. IC 50 values were calculated using GraphPad Prism software. The result of this work is summarized in Figure 14. 10 It is observed that the combination of Tipifarnib and FLT3 inhibitor Compound A increases the potency of FLT3 inhibitor Compound A two to three fold for both inhibition of FLT3 phosphorylation and MAP kinase phosphorylation. This is consistent with the increase in potency of the compounds anti-proliferative effects. 15 The effect of FLT3 phosphorylation that was observed with the FTI/ FLT3 inihbitor combination has not been reported previously. The mechanism for this effect on FLT3 phosphorylation is unknown but would be predicted to occur for any FTI/FLT3 inhibitor combination based on the experimental data collected for proliferation inhibition described above. 20 In Vitro BIOLOGICAL ACTIVITY MEASUREMENTS Reagents and Antibodies. Cell Titerglo proliferation reagent was obtained from 25 Promega Corporation. Proteases inhibitor cocktails and phosphatase inhibitor cocktails II were purchased from Sigma (St. Louis, MO). The GuavaNexin apoptosis reagent was purchased from Guava technologies (Hayward, CA). Superblock buffer and SuperSignal Pico reagent were purchased from Pierce Biotechnology (Rockford, IL). Fluorescence polarization tyrosine kinase kit (Green) was obtained from -30- -In-vitrogen. Mouse anti-phosphotytrosine (4Gl0) aitibody was purchased from Upstate Biotechnology, Inc (Charlottesville, VA). Anti-human FLT3 (rabbit IgG) was purchased from Santa Cruz biotechnology (Santa Cruz, CA). Anti-phospho Map kinase and total p42/4 4 Map kinase antibodies were purchased form Cell Signaling Technologies (Beverly, MA) Alkaline phosphatase-conjugated goat-anti-rabbit IgG, 209 WO 2006/135636 PCT/US2006/022142 and goat-anti-mouse IgG antibody purchased from Novagen (San Diego, CA). DDAO phosphate was purchased from Molecular Probes (Eugene, OR). All tissue culture reagents were purchase from BioWhitaker (Walkersville, MD). 5 Cell lines. THP-1 (Ras mutated, FLT3 wild type) and human MV4-11 (expressing constitutively FLT3-Internal tandem duplication or ITD mutant isolated from an AML patient with a t 15;17 translocation) AML cells)(see Drexler HG. The Leukemia Lymphoma Cell Line Factsbook. Academic Pres: San Diego, CA, 2000 and Quentmeier H, Reinhardt J, Zaborski M, Drexler HG. FLT3 mutations in acute 10 myeloid leukemia cell lines. Leukemia. 2003 Jan;17:120-124.) were obtained from ATCC (Rockville, MD). The IL-3 dependent murine B-cell progenitor cell line Baf3 expressing human wild-type FLT3 (Baf3-FLT3) and ITD-mutated FLT3 (Baf3-ITD) were obtained from Dr. Michael Heinrich (Oregon Health Sciences University). Cells were maintained in RPMI media containing penn/strep, 10% FBS alone (THP-1, 15 Baf3-ITD) and 2ng/ml GM-CSF (MV4-11) or 10ng/ml FLT ligand (Baf3 -FLT3). MV4-11, Baf3-ITD and Baf3-FLT3 cells are all absolutely dependent on FLT3 activity for growth. GM-CSF enhances the activity of the FLT3-ITD receptor in the MV4-11 cells. 20 Cell proliferation assay for MV4-11, Baf3-ITD, Baf3-FLT3 and THP-1 cells. To measure proliferation inhibition by test compounds the luciferase based CellTiterGlo reagent (Promega) was used. Cells are plated at 10,000 cells per well in 100ul of in RPMI media containing penn/strep, 10% FBS alone (THP-1, Baf3-ITD) and 0.2ng/ml GM-CSF (MV4-11) or 10ng/ml FLT ligand (Baf3 -FLT3). Compound dilutions or 25 0.1% DMSO (vehicle control) are added to cells and the cells are allowed to grow for 72 hours at standard cell growth conditions (37 0 C, 5%CO 2 ). In combination experiments test agents were added simultaneously to the cells. Total cell growth is quantified as the difference in luminescent counts (relative light units, RLU) of cell number at Day 0 compared-to total cell number- atDay 3-(72-hours of growth and/or 30 compound treatment). One hundred percent inhibition of growth is defined as an RLU equivalent to the Day 0 reading. Zero percent inhibition is defined as the RLU signal for the DMSO vehicle control at Day 3 of growth. All data points are an average of triplicate samples. The IC 50 for growth inhibition represents the dose of a 210 WO 2006/135636 PCT/US2006/022142 compound that results in a 50% inhibition of total cell growth at Day 3 of the DMSO vehicle control. ICs 50 data analysis was done with GraphPad Prism using a non-linear regression fit with a multiparameter, sigmoidal dose-response (variable slope) equation. 5 Immunoprecipitation and Quantitative Immunoblot Analysis. MV4-11 cells were grown in DMEM supplemented with 10% fetal bovine serum, 2ng/ml GM-CSF and kept between lx105 and 1 x106 cells/ml. For western blot analysis of Map Kinase phosphorylation 1X106 MV4-11 cells per condition were used. For 10 immunoprecipitation experiments examining FLT3-ITD phosphorylation, 1x10 7 cells were used for each experimental condition. After compound treatment, MV4-11 cells were washed once with cold lxPBS and lysed with HNTG lysis buffer (50 mM Hepes, 150 mM NaC1, 10% Glycerol, 1% Triton -X-100, 10 mM NaF, 1 mM EDTA, 1.5 mM MgC12, 10 mM NaPyrophosphate) + 4ul/ml Protease Inhibitor Cocktail 15 (Sigma cat.#P8340) + 4ul/ml Phosphatase Inhibitor Cocktail (Sigma Cat#P2850). Nuclei and debris were removed from cell lysates by centrifugation (5000rpm for 5 min. at 4oC). Cell lysates for immunoprecipitation were cleared with agarose-Protein A/G for 30 minutes at 4 0 C and immunoprecipitated using the 3ug of FLT3 antibody for 1 hours at 4 0 C. Immune complexes were then incubated with agarose-Protein A/G 20 for 1 hour at 4 0 C. Protein A/G immunoprecipitates were washed three times in 1.0 ml of HNTG lysis buffer. Immunoprecipitates and cell lysates (40ug total protein) were resolved on a 10% SDS-PAGE gel, and the proteins were transferred to nitrocellulose membrane. For anti-phosphotyrosine immunoblot analysis, membranes were blocked with SuperBlock (Pierce) and blotted for 2hours with anti-phosphotyrosine (clone 25 4G10, Upstate Biotechnologies) followed by alkaline phosphatase-conjugated goat anti-mouse antibody. For anti-phosphoMAP kinase western blotting, membranes were blocked Super block for 1 hour and blotted overnight in primary antibody, followed by an incubation with an AP conjugated goat-anti rabbit secondary antibody. Detection ofprotein was-doneby measuring-the-fluorescent product of the alkaline 30 phosphatase reaction with the substrate 9H-(1,3-dichloro-9,9- dimethylacridin-2-one 7-yl) phosphate, diammonium salt (DDAO phosphate) (Molecular Probes) using a Molecular Dynamics Typhoon Imaging system (Molecular Dynamics, Sunyvale, CA). Blots were stripped and reprobed with anti-FLT3 antibody for normalization of 211 WO 2006/135636 PCT/US2006/022142 phosphorylation signals. Quantitation of DDAO phosphate signal and IC 50 determinations were done with Molecular Dynamics ImageQuant and GraphPad Prism software. 5 Annexin V Staining. To examine the apoptosis of the leukemic MV4-11 cell line, cells were treated with Tipifarnib and/or FLT3 inhibitor Compound A, and Annexin V binding to phosphotidylserine on the outer leaflet of the plasma membrane of apoptotic cells was monitored using the GuavaNexin assay reagent and the Guava personal flow cytometry system (Guava Technologies; Hayward ,CA). MV4-1 1 cells 10 were plated at 200,000 cells per ml in tissue culture media containing varying concentrations of Tipifarnib and/or FLT3 inhibitor Compound A and incubated for 48hours at 37 0 C, 5%CO 2 . Cells were harvested by centrifugation at 400 x g for 10 minutes at 4 0 C. Cells were then washed with 1xPBS and resuspended in 1 x Nexin buffer at lx 106 cells/ml. 5g1 of Annexin V-PE ad 5g1 of 7-AAD was added to 401 of 15 cell suspension and incubated on ice for 20 minutes protected from light. 450ml of cold 1 x Nexin buffer was added to each sample and the cells were then acquired on the Guava cytometer according to the manufacturer's instructions. All annexin positive cells were considered apoptotic and percent Annexin positive cells was calculated. 20 Caspase 3/7 Activation Assay. MV4-11 cells were grown in RPMI media containing pen/strep, 10% FBS and 1 ng/mL GM-CSF. Cells were maintained between 2 x 10 5 cells/mL and 8 x 105 cells/mL feeding/splitting every 2-3 days. Cells were centrifuged and resuspend at 2 x 105 cells/mL RPMI media containing 25 Penn/Strep, 10% FBS and 0.1 ng/mL GM-CSF. MV4-11 cells were plated at 20,000 cells per well in 100 [tL of in RPMI media containing penn/strep, 10% FBS alone and 0.1 ng/mL GM-CSF (Corning Costar Cat # 3610) in the presence of various concentrations of test compounds or DMSO. In combination experiments test agents were added simultaneously to the cells. Cells were incubated for 24-hours-at 37 0 C, 5% 30 CO 2 . After 24-hour incubation, caspase activity was measured with the Promega CaspaseGlo reagent (Cat# G8090) according to the manufacture's instructions. Briefly, CaspaseGlo substrate is diluted with 10 mL Caspase Glo buffer. One volume of diluted Caspase Glo reagent was added to one volume of tissue culture media and 212 WO 2006/135636 PCT/US2006/022142 mixed for two minutes on rotating orbital shaker. Following incubation at room temperature for 60 minutes, light emission was measured on a Berthold luminometer with the 1 second program. Baseline caspase activity was defined as an RLU equivalent to DMSO vehicle (0.1% DMSO) treated cells. EC 50 data analysis was 5 completed with GraphPad Prism using a non-linear regression fit with a multiparameter, sigmoidal dose-response (variable slope) equation. Combination Index Analysis. To determine growth inhibition synergy of a FTI and FLT3 inhibitor combination based on the method of Chou and Talalay (Chou and 10 Talalay. See Chou TC, Talalay P. (1984) "Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors." Adv Enzyme Regul. 22:27-55.), fixed ratio combination dosing with isobolar statistical analysis was performed. Test agents were combined at a fixed ratio of the individual

IC

50 for proliferation for each cell line and dosed at varying concentrations including 15 9, 3, 1, 1/3, 1/9 times the determined IC 50 dose. To measure proliferation inhibition by test combinations the luciferase based CellTiterGlo reagent (Promega) was used. Cells are plated at 10,000 cells per well in 100ul of in RPMI media containing penn/strep, 10% FBS alone (THP-1, Baf3-ITD) and 0.1ng/ml GM-CSF (MV4-11) or 100ng/ml FLT ligand (Baf3 -FLT3). Total cell growth is quantified as the difference 20 in luminescent counts (relative light units, RLU) of cell number at Day 0 compared to total cell number at Day 3 (72 hours of growth and/or compound treatment). All data points are an average of triplicate samples. One hundred percent inhibition of growth is defined as an RLU equivalent to the Day 0 reading. Zero percent inhibition is defined as the RLU signal for the DMSO vehicle control at Day 3 of growth. 25 Inhibition data was analyzed using Calcsyn (BioSoft, Ferguson, MO) and the combination index (C.I.) calculated. C.I. values < 0.9 are considered synergistic. In vivo Combination Studies 30 The effect of combination treatment of the FLT3 Inhibitor FLT3 inhibitor compounds and Tipifarnib (ZarnestraTM) on the growth of MV-4-11 human AML tumor xenografts in nude mice was tested using FLT3 inhibitor Compounds B and D. The in vivo study was designed to extend the in vitro observations to evaluate the potential 213 WO 2006/135636 PCT/US2006/022142 for a synergistic anti-tumor effect of FLT3 inhibitor Compounds B and D each administered orally together with Tipifarnib to nude mice bearing established MV-4 11 tumor xenografts. 5 Anti-Tumor Effect of FLT3 Inhibitor Compound B Alone Female athymic nude mice (CD-1, nu/nu, 9-10 weeks old) were obtained from Charles River Laboratories (Wilmington, MA) and were maintained according to NIH standards. All mice were group housed (5 mice/cage) under clean-room conditions in 10 sterile micro-isolator cages on a 12-hour light/dark cycle in a room maintained at 21 22 'C and 40-50% humidity. Mice were fed irradiated standard rodent diet and water ad libitum. All animals were housed in a Laboratory Animal Medicine facility that is fully accredited by the American Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All procedures involving animals were 15 conducted in compliance with the NIH Guide for the Care and Use of Laboratory Animals and all protocols were approved by an Internal Animal Care and Use Committee (IACUC). The human leukemic MV4-11 cell line was obtained from the American Type Culture 20 Collection (ATCC Number: CRL-9591) and propagated in RPMI medium containing 10% FBS (fetal bovine serum) and 5 ng/mL GM-CSF (R&D Systems). MV4-11 cells are derived from a patient with childhood acute myelomonocytic leukemia with an 11q23 translocation resulting in a MLL gene rearrangement and containing an FLT3 ITD mutation (AML subtype M4)(1,2). MV4-11 cells express constitutively active 25 phosphorylated FLT3 receptor as a result of a naturally occurring FLT3/ITD mutation. Strong anti-tumor activity against MV4-11 tumor growth in the nude mouse tumor xenograft model is anticipated to be a desirable quality of the invention. In pilot growth studies, the following conditions were identified-as permitting MV4 30 11 cell growth in nude mice as subcutaneous solid tumor xenografts: Immediately prior to injection, cells were washed in PBS and counted, suspended 1:1 in a mixture of PBS:Matrigel (BD Biosciences) and then loaded into pre-chilled 1 cc syringes equipped with 25 gauge needles. Female athymic nude mice weighing no less than 214 WO 2006/135636 PCT/US2006/022142 20-21 grams were inoculated subcutaneously in the left inguinal region of the thigh with 5 x 106 tumor cells in a delivery volume of 0.2 mL. For regression studies, the tumors were allowed to grow to a pre-determined size prior to initiation of dosing. Approximately 3 weeks after tumor cell inoculation, mice bearing subcutaneous 5 tumors ranging in size from 106 to 439 mm 3 (60 mice in this range) were randomly assigned to treatment groups such that all treatment groups had similar starting mean tumor volumes of ~ 200 mm 3 . Mice were dosed orally by gavage with vehicle (control group) or compound at various doses twice-daily (b.i.d.) during the week and once-daily (q.d.) on weekends. Dosing was continued for 11 consecutive days, 10 depending on the kinetics of tumor growth and size of tumors in vehicle-treated control mice. If tumors in the control mice reached - 10% of body weight (~ 2.0 grams), the study was to be terminated. FLT3 inhibitor compounds were prepared fresh daily as a clear solution (@ 1, 3 and 10 mg/mL) in 20% HPI3CD/2%NMP/10mM Na Phosphate, pH 3-4 (NMP = Pharmasolve, ISP 15 Technologies, Inc.) or other suitable vehicle and administered orally as described above. During the study, tumor growth was measured three times-a-week (M, W, F) using electronic Vernier calipers. Tumor volume (mm 3 ) was calculated using the formula (L x W) /2, where L = length (mm) and W = width (shortest distance in mm) of the tumor. Body weight was measured three times-a-week and a loss of body 20 weight >10% was used as an indication of lack of compound tolerability. Unacceptable toxicity was defined as body weight loss > 20% during the study. Mice were closely examined daily at each dose for overt clinical signs of adverse, drug related side effects. 25 On the day of study termination, a final tumor volume and final body weight were obtained on each animal. Mice were euthanized using 100% CO 2 and tumors were immediately excised intact and weighed, with final tumor wet weight (grams) serving as a primary efficacy endpoint. 30 The time course of the inhibitory effects of FLT3 inhibitor compounds on the growth of MV4-11 tumors is illustrated in Figure 1. Values represent the mean (± sem) of 15 mice per treatment group. Percent inhibition (%I) of tumor growth was calculated versus tumor growth in the vehicle-treated Control group on the last study day. 215 WO 2006/135636 PCT/US2006/022142 Statistical significance versus Control was determined by Analysis of Variance (ANOVA) followed by Dunnett's t-test: * p <0.05; ** p <0.01. A similar reduction of final tumor weight was noted at study termination. (See Figure 5 2). Values represent the mean (+ sem) of 15 mice per treatment group, except for the high dose group where only 5 of 15 mice were sacrificed on the day of study termination. Percent Inhibition was calculated versus the mean tumor weight in the vehicle-treated control group. Statistical significance versus Control was determined by ANOVA followed by Dunnett's t-test: ** p < 0.01. 10 Figure 1: FLT3 inhibitor Compound B administered orally by gavage at doses of 10, 30 and 100 mg/kg b.i.d. for 11 consecutive days, produced statistically significant, dose-dependent inhibition of growth of MV4-11 tumors grown subcutaneously in nude mice. On the last day of treatment (Day 11), mean tumor volume was dose 15 dependently decreased by 44%, 84% (p< 0.01) and 94% (p< 0.01) at doses of 10, 30 and 100 mg/kg, respectively, compared to the mean tumor volume of the vehicle treated group. Tumor regression was observed at doses of 30 mg/kg and 100 mg/kg, with statistically significant decreases of 42% and 77%, respectively, versus the starting mean tumor volumes on Day 1. At the lowest dose tested of 10 mg/kg, 20 modest growth delay was observed (44%I vs Control), however this effect did not achieve statistical significance. Figure 2: Following eleven consecutive days of oral dosing, FLT3 inhibitor Compound B produced statistically significant, dose-dependent reductions of final 25 tumor weight compared to the mean tumor weight of the vehicle-treated group, with 48%, 85% (p <0.01) and 99% (p <0.01) decreases at 10, 30 and 100 mg/kg doses, respectively. In some mice, at the high dose of FLT3 inhibitor Compound B, final tumors had regressed to non-palpable, non-detectable tumors. 30 Mice were weighed three times each week (M, W, F) during the study and were examined daily at the time of dosing for overt clinical signs of any adverse, drug related side effects. No overt toxicity was noted for FLT3 inhibitor Compound B and no significant adverse effects on body weight were observed during the 11-day 216 WO 2006/135636 PCT/US2006/022142 treatment period at doses up to 200 mg/kg/day. Overall, across all dose groups for FLT3 inhibitor Compound B the mean loss of body weight was < 3% of initial body weight, indicating that the FLT3 inhibitor compounds were well-tolerated. 5 To establish further that FLT3 inhibitor compounds reached the expected target in tumor tissue, the level of FLT3 phosphorylation in tumor tissue obtained from vehicle- and compound-treated mice was measured. Results for FLT3 inhibitor Compound B is shown in Figure 3. For this pharmacodynamic study, a sub-set of 10 mice from the vehicle-treated control group were randomized into two groups of 5 10 mice each and then treated with another dose of vehicle or compound (100 mg/kg, po). Tumors were harvested 2 hours later and snap frozen for assessment of FLT3 phosphorylation by immunobloting. Harvested tumors were processed for immunoblot analysis of FLT3 phosphorylation 15 in the following manner: 100 mg of tumor tissue was dounce homogenized in lysis buffer (50 mM Hepes, 150 mM NaC1, 10% Glycerol, 1% Triton -X-100, 10 mM NaF, 1 mM EDTA, 1.5 mM MgCl 2 , 10 mM NaPyrophosphate) supplemented with phosphatase (Sigma Cat# P2850) and protease inhibitors (Sigma Cat #P8340). Insoluble debris was removed by centrifugation at 1000 x g for 5 minutes at 4 'C. 20 Cleared lysates (15mg of total potein at 10mg/ml in lysis buffer) were incubated with 10gg of agarose conjugated anti-FLT3 antibody, clone C-20 (Santa Cruz cat # sc 479ac), for 2 hours at 4 oC with gentle agitation. Immunoprecipitated FLT3 from tumor lysates were then washed four times with lysis buffer and separated by SDS PAGE. The SDS-PAGE gel was transfered to nitrocellulose and immunoblotted with 25 anti-phosphotyrosine antibody (clone-4G10, UBI cat. #05-777), followed by alkaline phosphatase-conjugated goat anti-mouse secondary antibody (Novagen cat. # 401212). Detection of protein was done by measuring the fluorescent product of the alkaline phosphatase reaction with the substrate 9H-(1,3-dichloro-9,9 dimethylacridin-2-one-7-yl)_phosphate ,-diammonium-salt (DDAO phosphate) 30 (Molecular Probes cat. # D 6487) using a Molecular Dynamics Typhoon Imaging system (Molecular Dynamics, Sunyvale, CA). Blots were then stripped and reprobed with anti-FLT3 antibody for normalization of phosphorylation signals. 217 WO 2006/135636 PCT/US2006/022142 As illustrated in Figure 3, a single dose of FLT3 inhibitor Compound B at 100 mg/kg produced a biologically significant reduction in the level of FLT3 phosphorylation in MV4-11 tumors compared to tumors from vehicle-treated mice. (Total FLT3 is shown in the bottom plot.) These results further demonstrate that the comounds of the 5 present invention are in fact interacting with the expected FLT3 target in the tumor. MV-4-11 tumor-bearing nude mice were prepared as described above, in the aforementioned in vivo evaluation of the oral anti-tumor efficacy of FLT3 inhibitor Compound B. 10 Anti-Tumor Effect of FLT3 Inhibitor Compound B Administered with Tipifarnib MV-4-11 tumor-bearing nude mice were prepared as described above, in the aforementioned in vivo evaluation of the oral anti-tumor efficacy of FLT3 inhibitor 15 Compound B alone. Nude mice with MV-4-11 tumors were randomized to five treatment groups of 15 mice each with mean tumor size was equivalent in each treatment group. Tumor volume (mm3) was calculated using the formula (L x W)2/2, where L = length (mm) 20 and W = width (shortest distance in mm) of the tumor. The starting mean tumor volume for each treatment group was approximately 250 mm3. Mice were dosed orally twice-daily (bid) during the week and once-daily (qd) on weekends with either Vehicle (20% HPBCD/2%NMP/10mM Na Phosphate, pH 3-4 25 (NMP = Pharmasolve, ISP Technologies, Inc.), a sub-efficacious dose of FLT3 inhibitor Compound B (10 mg/kg), an-efficacious dose of FLT3 inhibitor Compound B (20 mg/kg) and Tipifarnib (50 mg/kg) alone or in combination with each dose of FLT3 inhibitor Compound B. Dosing was continued for nine consecutive days. Tumor growth was measured three times during the studyusing 30 electronic Vernier calipers. Body weight was measured three times during the study and a loss of body weight >10% was used as an indication of lack of compound tolerability. 218 WO 2006/135636 PCT/US2006/022142 The time course of the effect of treatment with FLT3 inhibitor Compound B and Tipifarnib alone and in combination on the growth of MV-4-11 tumors is illustrated in Figure 15.. As shown, FLT3 inhibitor Compound B administered at a dose of 10 mg/kg bid produced marginal significant inhibition of tumor growth compared to the 5 Vehicle-treated group that reached tumors volumes of approximately 800 mm 3 . FLT3 inhibitor' Compound B administered at a dose of 20 mg/kg bid provided significant inhibition of tumor growth compared to the Vehicle-treated group and completely controlled tumor growth compared to the control. This dose was observed to produce tumor growth stasis but induced no tumor regression (defined as a tumor size less than 10 the tumor size at study initiation). As illustrated in Figure 15, on the final day of treatment (Day 9), tumor volume was not significantly reduced by Tipifarnib (50 mg/kg) alone when compared to control Values represent the mean (±t sem) of 15 mice per treatment group. Percent inhibition of tumor growth was calculated versus tumor growth in the Vehicle-treated Control group on the last study day. Statistical 15 significance versus Control was determined by ANOVA followed by Dunnett's t-test: * p < 0

.

0 1. Again as shown in Figure 15, Tipifarnib administered as a single agent at a dose of 50 mg/kg was ineffective. However, when both agents were administered orally in 20 combination, there was a statistically significant regression of tumor volume from the mean starting tumor volume on Day 1 when FLT3 inhibitor Compound B was administered at either 10 or 20 mg/kg. On day 9, the mean tumor volume of the group was inhibited by 95% compared to the Vehicle-treated control group. Thus, combination treatment produced an inhibitory effect (ie. tumor regression) that was 25 much greater than either agent administered alone. In point of fact, Tipifarnib (50 mg/kg) and FLT3 inhibitor Compound B alone at 10 mg/kg were essentially inactive while the combination, remarkably provided essentially complete tumor regression. Figure 15 illustrates the effects on tumor volume of orally administered-FLT-3 30 inhibitor Compound Compound B and Tipifarnib alone or in combination on the growth of MV-4-11 tumor xenografts in nude mice. 219 WO 2006/135636 PCT/US2006/022142 Figure 16 illustrates the effects of orally administered FLT3 inhibitor Compound B and Tipifarnib alone or in combination on the final volume of MV-4-11 tumor xenografts in nude mice on the final study day. As shown in Figure 16, at study termination, synergy was noted with combination treatment when the final tumor 5 volumes of each treatment group were compared with the exception that the final tumor weight reached statistical significance. Figure 17 illustrates the effects of orally administered FLT3 inhibitor Compound B and Tipifarnib alone or in combination on the final tumor weight of MV-4-11 tumor 10 xenografts in nude mice on the terminal study day. As shown in Figure 17, at study termination, synergy was confirmed by tumor weight measurement in the 10 mg/kg FLT3 inhibitor Compound B/50 mg/kg Tipifarnib combination treatment group when compared to the final tumor weight of the appropriate treatment group when the agents were administered alone. 15 No overt toxicity was noted and no significant adverse effects on body weight were observed during the 9-day treatment period with either agent alone or in combination. In summary, combination treatment with FLT3 inhibitor Compound B and Tipifarnib produced significantly greater inhibition of tumor growth compared to either FLT3 20 inhibitor Compound B or Tipifarnib administered alone. Anti-Tumor Effect of FLT3 Inhibitor Compound D Alone The oral anti-tumor efficacy of FLT3 inhibitor Compound D of the present invention 25 was evaluated in vivo using a nude mouse MV4-11 human tumor xenograft regression model in athymic nude mice using the method as described above, in the aforementioned in vivo evaluation of the oral anti-tumor efficacy of FLT3 inhibitor Compound B. 30 MV-4-11 tumor-bearing nude mice were prepared as described above, in the aforementioned in vivo evaluation of the oral anti-tumor efficacy of FLT3 inhibitor Compound B alone. 220 WO 2006/135636 PCT/US2006/022142 Female athymic nude mice weighing no less than 20-21 grams were inoculated subcutaneously in the left inguinal region of the thigh with 5 x 106 tumor cells in a delivery volume of 0.2 mL. For regression studies, the tumors were allowed to grow to a pre-determined size prior to initiation of dosing. Approximately 3 weeks after 5 tumor cell inoculation, mice bearing subcutaneous tumors ranging in size from 100 to 586 mm 3 (60 mice in this range; mean of 288 ± 133 mm 3 (SD) were randomly assigned to treatment groups such that all treatment groups had statistically similar starting mean tumor volumes (mm 3 ). Mice were dosed orally by gavage with vehicle (control group) or compound at various doses twice-daily (b.i.d.) during the week and 10 once-daily (qd) on weekends. Dosing was continued for 11 consecutive days, depending on the kinetics of tumor growth and size of tumors in vehicle-treated control mice. If tumors in the control mice reached - 10% of body weight (- 2.0 grams), the study was to be terminated. FLT3 inhibitor Compound D was prepared fresh daily as a clear solution (@ 1, 5 and 10 mg/mL) in 20% HPBCD/D5W, pH 3-4 15 or other suitable vehicle and administered orally as described above. During the study, tumor growth was measured three times-a-week (M, W, F) using electronic Vernier calipers. Tumor volume (mm 3 ) was calculated using the formula (Lx W) 2 /2, where L = length (mm) and W = width (shortest distance in mm) of the tumor. Body weight was measured three times-a-week and a loss of body weight >10% was used as 20 an indication of lack of compound tolerability. Unacceptable toxicity was defined as body weight loss > 20% during the study. Mice were closely examined daily at each dose for overt clinical signs of adverse, drug-related side effects. On the day of study termination (Day 12), a final tumor volume and final body weight 25 were obtained on each animal. Mice were euthanized using 100% CO 2 and tumors were immediately excised intact and weighed, with final tumor wet weight (grams) serving as a primary efficacy endpoint. The time course ofthe inhibitory effects of fLT3 inhibitor Compound D-of the 30 present invention on the growth of MV4-11 tumors is illustrated in Figure 18. Values represent the mean (± sem) of 15 mice per treatment group. Percent inhibition (%I) of tumor growth was calculated versus tumor growth in the vehicle-treated Control 221 WO 2006/135636 PCT/US2006/022142 group on the last study day. Statistical significance versus Control was determined by Analysis of Variance (ANOVA) followed by Dunnett's t-test: * p <0.05; ** p <0.01. As seen in Figure 18, FLT3 inhibitor Compound D of the present invention, 5 administered orally by gavage at doses of 10, 50 and 100 mg/kg b.i.d. for 11 consecutive days, produced statistically significant, dose-dependent inhibition of growth of MV4-11 tumors grown subcutaneously in nude mice. On the last day of treatment (Day 11), mean tumor volume was dose-dependently decreased with nearly 100% inhibition (p < 0.001) at doses of 50 and 100 mg/kg, compared to the mean 10 tumor volume of the vehicle-treated group. FLT3 inhibitor Compound D of the present invention produced tumor regression at doses of 50 mg/kg and 100 mg/kg, with statistically significant decreases of 98% and 93%, respectively, versus the starting mean tumor volumes on Day 1. At the lowest dose tested of 10 mg/kg, no significant growth delay was observed compared to the vehicle-treated control group. 15 When dosing was stopped on Day 12 in the 100 mg/kg treated dose group and the tumor was allowed to re-grow, only 6/12 mice showed papable, measureable tumor on study day 34. FLT3 inhibitor Compound D of the present invention produced virtually complete 20 regression of tumor mass as indicated by no measurable remant tumor at study termination. (See Figure 19). Bars on the graph of Figure 19 represent the mean (+ sem) of 15 mice per treatment group. As shown, there was no significant decrease in final tumor weight at the 10 mg/kg dose, consistent with the tumor volume data in Figure 18. At the dose of 50 mg/kg, there is no bar represented on the graph since 25 there was no measurable tumor mass detectable in these mice at termination, consistent with the complete regression of tumor volume noted in Figure 18. The 100 mg/kg dose group is not represented on this graph since these mice were taken off drug and remnant tumor was allowed to regrow as stated above. 30 Following eleven consecutive days of oral dosing, FLT3 inhibitor Compound D of the present invention produced dose-dependent reductions of final tumor weight compared to the mean tumor weight of the vehicle-treated group, with complete regression of tumor mass noted at the 50 mg/kg dose. (See Figure 19). 222 WO 2006/135636 PCT/US2006/022142 Mice were weighed three times each week (M, W, F) during the study and were examined daily at the time of dosing for overt clinical signs of any adverse, drug related side effects. No overt toxicity was noted for FLT3 inhibitor Compound D of 5 the present invention and no significant adverse effects on body weight were observed during the 11-day treatment period at doses up to 200 mg/kg/day (See Figure 20). Overall, across all dose groups, there was no significant loss of body weight compared to the starting body weight, indicating that FLT3 inhibitor Compound D of the present invention was well-tolerated. 10 To establish further that FLT3 inhibitor Compound D of the present invention reached the expected target in tumor tissue, the level of FLT3 phosphorylation in tumor tissue obtained from vehicle- and compound-treated mice was measured. Results for FLT3 inhibitor Compound D of the present invention are shown in Figure 21. For this 15 pharmacodynamic study, a sub-set of 6 mice from the vehicle-treated control group were randomized into three groups of 2 mice each and then treated with another dose of vehicle or compound (10 and100 mg/kg, po). Tumors were harvested 6 hours later and snap frozen for assessment of FLT3 phosphorylation by western blots. 20 Harvested tumors were frozen and processed for immunoblot analysis of FLT3 phosphorylation in the following manner: 200 mg of tumor tissue was dounce homogenized in lysis buffer (50 mM Hepes, 150 mM NaC1, 10% Glycerol, 1% Triton -X-100, 10 mM NaF, 1 mM EDTA, 1.5 mM MgC1 2 , 10 mM NaPyrophosphate) supplemented with phosphatase (Sigma Cat# P2850) and protease inhibitors (Sigma 25 Cat #P8340). Insoluble debris was removed by centrifugation at 1000 x g for 5 minutes at 4 'C. Cleared lysates (15mg of total potein at 10mg/ml in lysis buffer) were incubated with 10gg of agarose conjugated anti-FLT3 antibody, clone C-20 (Santa Cruz cat # sc-479ac), for 2 hours at 4 oC with gentle agitation. 30 Immunoprecipitated FLT3 from tumor lysates were then washed four times with lysis buffer and separated by SDS-PAGE. The SDS-PAGE gel was transfered to nitrocellulose and immunoblotted with anti-phosphotyrosine antibody (clone-4G10, UBI cat. #05-777), followed by alkaline phosphatase-conjugated goat anti-mouse 223 WO 2006/135636 PCT/US2006/022142 secondary antibody (Novagen cat. # 401212). Detection of protein was done by measuring the fluorescent product of the alkaline phosphatase reaction with the substrate 9H-(1,3-dichloro-9,9- dimethylacridin-2-one-7-yl) phosphate, diammonium salt (DDAO phosphate) (Molecular Probes cat. # D 6487) using a Molecular 5 Dynamics Typhoon Imaging system (Molecular Dynamics, Sunyvale, CA). Blots were then stripped and reprobed with anti-FLT3 antibody for normalization of phosphorylation signals. As illustrated in Figure 21, a single dose of FLT3 inhibitor Compound D of the 10 present invention at 100 mg/kg produced a biologically significant reduction in the level of FLT3 phosphorylation (top panel, tumor 5 and 6) in MV4-11 tumors compared to tumors from vehicle-treated mice (tumor 1 and 2). (Total FLT3 is shown in the bottom plot.) There was also a partial reduction of phosphorylation in animals treated with 10mg/kg of the compound (tumor 3-4). These results further demonstrate 15 that the compound of the present invention is in fact interacting with the expected FLT3 target in the tumor. Anti-Tumor Effect of FLT3 Inhibitor Compound D Administered with Tipifarnib 20 To demonstrate in vivo synergy of the combination of FLT3 inhibitor Compound D and Tipifarnib in MV-4-11 xenograft model, tumor-bearing nude mice were prepared as described above, in the aforementioned in vivo evaluation of the oral anti-tumor efficacy of FLT3 inhibitor Compound B alone. 25 Nude mice with MV-4-11 tumors were randomized to four treatment groups of 10 mice each with mean tumor size was equivalent in each treatment group. Tumor volume (mm3) was calculated using the formula (L x W)2/2, where L = length (mm) and W = width (shortest distance in mm) of the tumor. The starting mean tumor volume for each treatment group was approximately 250 mm3. 30 Mice were dosed orally twice-daily (bid) during the week and once-daily (qd) on weekends with either Vehicle (20% HPB-CD, pH 3-4) or sub-efficacious doses of FLT3 inhibitor Compound D (25 mg/kg) or Tipifarnib (50 mg/kg) alone or in 224 WO 2006/135636 PCT/US2006/022142 combination. Dosing was continued for sixteen consecutive days. Tumor growth was measured three times-a-week (Monday, Wednesday, Friday) using electronic Vernier calipers. Body weight was measured three times-a-week and a loss of body weight >10% was used as an indication of lack of compound tolerability. 5 The time course of the effect of treatment with FLT3 inhibitor Compound D and Tipifarnib alone and in combination on the growth of MV-4-11 tumors is illustrated in Figure 22. As shown, FLT3 inhibitor Compound D administered at a dose of 25 mg/kg bid produced stasis of tumor growth compared to the Vehicle-treated group 10 which reached tumors volumes of approximately 1500 mm 3 . As illustrated in Figure 22, on the final day of treatment (Day 16), tumor volume was significantly inhibited by 76% compared to the vehicle-treated control group. Values represent the mean (_ sem) of 10 mice per treatment group. Percent inhibition of tumor growth was calculated versus tumor growth in the Vehicle-treated Control group on the last study 15 day. Statistical significance versus Control was determined by ANOVA followed by Dunnett's t-test: * p < 0.01. As shown in Figure 22, Tipifarnib administered as a single agent at a dose of 50 mg/kg was ineffective. However, when both agents were administered orally in 20 combination, there was a statistically significant regression of tumor volume from the mean starting tumor volume on Day 1. On day 16, the mean tumor volume of the group was inhibited by 95% compared to the Vehicle-treated control group. Thus, combination treatment produced an inhibitory effect (ie. tumor regression) that was approximately 1.3 times the additive effect of each agent given alone, indicating 25 synergy (see Figure 22). Figure 23 illustrates the effects on tumor volume of orally administered FLT3 inhibitor Compound D and Tipifarnib alone or in combination on the growth of MV 4-11 tumor xenografts in nude mice._ Figure 24 illustrates the effects of orally 30 administered FLT3 inhibitor Compound D and Tipifarnib alone or in combination on the final weight of MV-4-11 tumor xenografts in nude mice. As shown in Figure 24, at study termination, similar synergy was noted with combination treatment when the final tumor weights of each treatment group were compared. 225 WO 2006/135636 PCT/US2006/022142 No overt toxicity was noted and no significant adverse effects on body weight were observed during the 16-day treatment period with either agent alone or in combination. Plasma and tumor samples were collected two hours after the last dose 5 of compounds for determination of drug levels. In summary, combination treatment with FLT3 inhibitor Compound D and Tipifarnib produced significantly greater inhibition of tumor growth compared to either FLT3 inhibitor Compound D or Tipifarnib administered alone. 10 CONCLUSIONS Herein we provide significant evidence that the combination of an FTI and a FLT3 inhibitor synergistically inhibits the growth of and induces the death of FLT3 dependent cells in vitro and in vivo (such as AML cells derived from patients with 15 FLT3-ITD mutations). In vitro studies, in multiple FLT3-dependent cell lines, demonstrated synergistic inhibition of AML cell proliferation with the FTI/FLT3 inhibitor combination by both the combination index method of Chou and Talalay and the median effect method using a combination of single sub-optimal doses of each compound. Additionally, the combination of an FTI and a FLT3 inhibitor induced 20 dramatic cell death in FLT3-dependent AML cells. This effect on apoptotsis induction was significantly greater than either agent alone. This synergistic effect of an FTI/FLT3 inhibitor combination was observed for multiple, structurally distinct FLT3 inhibitors and two different FTIs. Accordingly, this synergistic inhibition of proliferation and induction of apoptosis would occur for any FLT3 inhibitor/FTI 25 combination. Interestingly, the combination of the FTI Tipifarnib with a FLT3 inhibitor significantly increases the potency of FLT3 inhibitor mediated decrease in FLT3 receptor signaling. Furthermore, the synergy observed using in vitro methods was recapitulated in an in vivo tumor model using FLT3-dependent AML cells (MV4 11) with the combination of the FTI Tipifarnib and two chemically distinct FLT3 30 inhibitors (FLT3 inhibitor Compounds B and D). Accordingly, this effect would be seen for any FLT3 inhibitor/ FTI combination. To our knowledge, this is the first time that synergistic AML cell killing has been observed with the combination of an FTI and a FLT3 inhibitor. Additionally, the synergies observed in the combination 226 WO 2006/135636 PCT/US2006/022142 were not obvious to those skilled in the art based on previous data. The observed synergy is likely related to FTIs known inhibition small GTPase (Ras and Rho) and NfkB driven proliferation and survival and the FLT3 inhibitors' ability to decrease proliferation and survival signaling by the FLT3 receptor. Additionally, the 5 FTI/FLT3 inhibitor combination had significant effects on the activity of the FLT3, receptor itself. Although the mechanism for this is currently unknown, it is likely to have a significant role in both the inhibition of cell proliferation and activation of cell death observed with the FLT3 inhibitor/ FTI combination. In sum, these studies represent a novel treatment paradigm for FLT3 disorders, particularly hematological 10 malignancies expressing wild-type or mutant FLT3 and the basis for the design of clinical trials to test FTI and FLT3 inhibitor combinations for the treatment of FLT3 disorders, particularly AML, ALL and MDS. While the foregoing specification teaches the principles of the present invention, with 15 examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. 227

Claims

1. A method of reducing or inhibiting FLT3 tyrosine kinase expression or activity in a subject comprising the administration of a FLT3 kinase inhibitor and a 5 farnesyl transferase inhibitor to the subject, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': B R X R N Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, 10 wherein: qis0, 1 or2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; 15 Z is NH, N(alkyl), or CH

2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R, and R 2 are independently selected from the following: Y 24.Ra / Ra Ra Ra -- Rbb 20 (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; Yis a-direct bond,-0, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 , hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R 5 , 25 pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with R 5 , cyclic heterodionyl optionally substituted with R 5 , 228 WO 2006/135636 PCT/US2006/022142 heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO

3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; 5 Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C(1-4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, 10 or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 15 R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated 20 alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, or alkylamino. 25 2. A method of treating disorders related to FLT3 tyrosine kinase expression or activity in a subject comprising the administration of a FLT3 kinase inhibitor and a farnesyl transferase inhibitor to the subject, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': 229 WO 2006/135636 PCT/US2006/022142 B Q N q R2 N Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis 0, 1 or2; 5 p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a 10 nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: Y Ra Ra n R a Ra -1-Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) . wherein n is 1, 2, 3 or 4; 15 Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 , hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, 20 heterocyclyl optionally substituted with R 5 , squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRWSO 2 RY, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; 230 WO 2006/135636 PCT/US2006/022142 Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C( 1 .- 4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, 5 or heteroaralkyl, or Rw and R. may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 10 R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated 15 alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. 20 3. A method for preventing in a subject a cell proliferative disorder, comprising administering to the subject a prophylactically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, 25 wherein said FLT3-kinase inhibitor comprises a compound of Formula I': R 3 Z O "x 2 Formula I 231 WO 2006/135636 PCT/US2006/022142 and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis 0, 1 or2; pis 0 or 1; 5 Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or 10 heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: nn Y n R a Ra R a Ra -1-Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); 15 Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with RS, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, 20 -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(0)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from: halogen, 25 cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, -C(1-4)alkyl-OH, or alkylamino; RwandRx are independently.selected from: hydrogen,-alkyl,-alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, 30 N(alkyl), SO, SO 2 , or S; 232 WO 2006/135636 PCT/US2006/022142 Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl 5 optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, 10 trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino.

4. The method of claim 3 further comprising administering to the subject a prophylactically effective amount of chemotherapy. 15

5. The method of claim 3 further comprising administering to the subject a prophylactically effective amount of radiation therapy.

6. The method of claim 3 further comprising administering to the subject a 20 prophylactically effective amount of gene therapy.

7. The method of claim 3 further comprising administering to the subject a prophylactically effective amount of immunotherapy. 25

8. A method for preventing in a subject a cell proliferative disorder, comprising administering to the subject a prophylactically effective amount of a pharmaceutical composition comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': 30 233 WO 2006/135636 PCT/US2006/022142 B RR X R2 R 2 Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis0, 1 or2; 5 p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a 10 nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: Y' R a a Ra Ra --Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) . wherein n is 1, 2, 3 or 4; 15 Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R 5 , pyrrolidinonyl optionally substituted with R 5 , piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, 20 heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy,- -SOI Ry, -NRwSO 2 Ry, - -NRwSO 2 Rx, -SOiRy, -OSO2NRwRx, or -S0 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; 234 WO 2006/135636 PCT/US2006/022142 Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C(1.4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, 5 or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 10 R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R4, heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated 15 alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. 20

9. The method of claim 8 further comprising administering to the subject a prophylactically effective amount of chemotherapy.

10. The method of claim 8 further comprising administering to the subject a prophylactically effective amount of radiation therapy. 25

11. The method of claim 8 further comprising administering to the subject a prophylactically effective amount of gene therapy.

12._ The method of claim 8 further comprising administering to the subject a 30 prophylactically effective amount of immunotherapy.

13. A method for preventing in a subject a disorder related to FLT3, comprising administering to the subject a prophylactically effective amount of (1) a first 235 WO 2006/135636 PCT/US2006/022142 pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': 5 B R, Z O N)q N R IX R N Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis0, 1 or2; 10 p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a 15 nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: YnRa / Ra Ra Ra -Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; 20 Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 , hydroxyl, alkylamino,- dialk-ylamino,-oxazolidinonyl optionally-sibstituted with R 5 , pyrrolidinonyl optionally substituted with R 5 , piperidinonyl optionally substituted with R 5 , cyclic heterodionyl optionally substituted with R 5 , 25 heterocyclyl optionally substituted with R 5 , squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, 236 WO 2006/135636 PCT/US2006/022142 -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from: halogen, 5 cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C( 1 -4)alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, 10 N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl 15 optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R4, phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, 20 trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino.

14. The method of claim 13 further comprising administering to the subject a prophylactically effective amount of chemotherapy. 25

15. The method of claim 13 further comprising administering to the subject a prophylactically effective amount of radiation therapy.

16. The method of claim 13 further comprising administering to the subject a 30 prophylactically effective amount of gene therapy.

17. The method of claim 13 further comprising administering to the subject a prophylactically effective amount of immunotherapy. 237 WO 2006/135636 PCT/US2006/022142

18. A method for preventing in a subject a disorder related to FLT3, comprising administering to the subject a prophylactically effective amount of a pharmaceutical composition comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a 5 pharmaceutically acceptable carrier, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': B R3, Z OAQq N R 2 N Formnula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, 10 wherein: qis0, 1 or2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; 15 Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: Y Y Ra n .Ra Ra Ra Rb b 20 (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; Y is a direct bond,- O,S,-NH,-or N(alkyl);. Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, 25 pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, 238 WO 2006/135636 PCT/US2006/022142 heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; 5 Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl)2, alkyl, -C(I 4 )alkyl-OH, or alkylamino; R, and R,, are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, 10 or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and 15 R 3 is one or more substituents, optionally present, arid independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R4, alkylamino, heterocyclyl optionally substituted with R4, alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated 20 alkyl, heteroaryloxy optionally substituted with R4, dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. 25

19. The method of claim 18 further comprising administering to the subject a prophylactically effective amount of chemotherapy.

20. The method of claim 18 further comprising administering to the subject a prophylactically effective amount of radiation therapy.

21. The method of claim 18 further comprising administering to the subject a prophylactically effective amount of gene therapy. 239 WO 2006/135636 PCT/US2006/022142

22. The method of claim 18 further comprising administering to the subject a prophylactically effective amount of immunotherapy.

23. A method of treating in a subject a cell proliferative disorder, comprising 5 administering to the subject a therapeutically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': 10 B R3r&Z 0 AQk N R X R2 Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis0, 1 or2; 15 pis 0 or l; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a 20 nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; Rx and 112 are independently selected from the following: nR a Ra R Ra /R Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; 25 Y is a direct bond, O, S, NH, or N(alkyl); 240 WO 2006/135636 PCT/US2006/022142 Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, 5 heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; 10 Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, -C(1- 4 )alkyl-OH, or alkylamino; Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and Rx may optionally be taken together to form a 5 to 15 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and R 3 is one or more substituents, optionally present, and independently selected from: 20 alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or 25 -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino.

24. The method of claim 23 further comprising administering to the subject a 30 therapeutically effective amount of chemotherapy.

25. The method of claim 23 further comprising administering to the subject a therapeutically effective amount of radiation therapy. 241 WO 2006/135636 PCT/US2006/022142

26. The method of claim 23 further comprising administering to the subject a therapeutically effective amount of gene therapy. 5

27. The method of claim 23 further comprising administering to the subject a therapeutically effective amount of immunotherapy.

28. A method of treating in a subject a cell proliferative disorder, comprising administering to the subject a therapeutically effective amount of a pharmaceutical 10 composition comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': B RR Z R2 ' Formnula I 15 and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis 0, 1 or2; p is 0 or 1; Q is NH, N(alkyl), O, or a direct bond; 20 X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl,-providedthat B is-not-thiadiaziny; 25 R 1 and R 2 are independently selected from the following: -WRa n SY R a ,Ra R a Ra "-Rbb n 'VWn (a-1), (a-2), (a-3), (a-4), or (a-5) 242 WO 2006/135636 PCT/US2006/022142 wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); R, is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 , hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, 5 pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(R,)CORy, -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or 10 -S0 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; R 5 is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, -C(1.4)alkyl-OH, or alkylamino; 15 Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and R,, may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, 20 heteroaralkyl, or heteroaryl; and R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R4, 25 phenoxy optionally substituted with R4, -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R4, dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl),a alkyloralkylamino. 30

29. The method of claim 28 further comprising administering to the subject a therapeutically effective amount of chemotherapy. 243 WO 2006/135636 PCT/US2006/022142

30. The method of claim 28 further comprising administering to the subject a therapeutically effective amount of radiation therapy.

31. The method of claim 28 further comprising administering to the subject a 5 therapeutically effective amount of gene therapy.

32. The method of claim 28 further comprising administering to the subject a therapeutically effective amount of immunotherapy. 10

33. A method of treating in a subject a disorder related to FLT3, comprising administering to the subject a therapeutically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, 15 wherein the FLT3 kinase inhibitor comprises a compound of Formula I': B R 3 , Z N )q N R X R2N Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: 20 q is 0, 1 or 2; pis 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH,-N(alkyl); or CH 2 ; 25 B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a nine to ten membered benzo-fused heterocyclyl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: 244 WO 2006/135636 PCT/US2006/022142 Y Ra /~S Ra Ra R a -- Rbb (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 , hydroxyl, 5 alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)OR,., -N(R,)CORy, 10 -SRy, -SORy, -SO 2 Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, 15 -C(0)N(alkyl) 2 , alkyl, -C(_4)alkyl-OH, or alkylamino; Rw and R,, are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and R, may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; 20 R, is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and R 3 is one or more substituents, optionally present, and independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with 25 R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R4, -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxyoptionally substituted withR4, dialkylamino, --NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, 30 -C(O)N(alkyl) 2 , alkyl, or alkylamrnino. 245 WO 2006/135636 PCT/US2006/022142

34. The method of claim 33 further comprising administering to the subject a therapeutically effective amount of chemotherapy.

35. The method of claim 33 further comprising administering to the subject a 5 therapeutically effective amount of radiation therapy.

36. The method of claim 33 further comprising administering to the subject a therapeutically effective amount of gene therapy. 10

37. The method of claim 33 further comprising administering to the subject a therapeutically effective amount of immunotherapy.

38. A method of treating in a subject a disorder related to FLT3, comprising administering to the subject a therapeutically effective amount of a pharmaceutical 15 composition comprising a FLT3 kinase inhibitor, a farnesyl transferase inhibitor and a pharmaceutically acceptable carrier, wherein the FLT3 kinase inhibitor comprises a compound of Formula I': B Rz Z N R X R2 N Formula I 20 and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis0, 1 or2; p is 0 or 1; Q-isNl-,_N(alkyl),-O, or a direct bond; 25 X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; 246 WO 2006/135636 PCT/US2006/022142 B is selected from: cycloalkyl, a nine to ten membered benzo-fused heteroaryl, or a nine to ten membered benzo-fused heterocyclyl, or, if R3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; R 1 and R 2 are independently selected from the following: ;Y nRa / Ra Ra a -Rbb 'n n Ra -Rbb 5 (a-1), (a-2), (a-3), (a-4), or (a-5) wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, 10 pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, cyclic heterodionyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy, -SO2Ry, -NRwSO 2 Ry, -NRwSO 2 Rx, -SO 3 Ry, -OSO 2 NRwRx, or 15 -SO 2 NRwRx; Rbb is hydrogen, halogen, alkoxy, phenyl, heteroaryl, or heterocyclyl; R 5 is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, -C(1-4)alkyl-OH, or alkylamino; 20 Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or Rw and R,, may optionally be taken together to form a 5 to 7 membered ring, optionally containing a heteromoiety selected from O, NH, N(alkyl), SO, SO 2 , or S; RY is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, 25 heteroaralkyl, or heteroaryl; and R 3 is one or more substituents, optionally present, and independently selected from: -alkyl,-alkoxyhalogen,-nitro;,-cycloalkyl optionally-substituted-with R 4 ,-heteroaryl optionally substituted with R4, alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R4, 30 phenoxy optionally substituted with R4, -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R4, dialkylamino, -NHSO 2 alkyl, or 247 WO 2006/135636 PCT/US2006/022142 -SO 2 alkyl; wherein R4 is independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino. 5

39. The method of claim 38 further comprising administering to the subject a therapeutically effective amount of chemotherapy.

40. The method of claim 38 further comprising administering to the subject a therapeutically effective amount of radiation therapy. 10

41. The method of claim 38 further comprising administering to the subject a therapeutically effective amount of gene therapy.

42. The method of claim 38 further comprising administering to the subject a 15 therapeutically effective amount of immunotherapy.

43. The method of claim 38 further comprising administering to the subject a therapeutically effective amount of chemotherapy. 20

44. A method as defined in any of claims 1-43, wherein the farnesyl transferase inhibitor comprises a compound of formula (I): R 3 R 16 R 4 R17 Rg -R 6 SR19 1 R7 R, (I) a-stereoisomeric-fori- thereof, a Phairiiceuticaflyi-acceptable acid or base 25 addition salt thereof, wherein the dotted line represents an optional bond; X is oxygen or sulfur; 248 WO 2006/135636 PCT/US2006/022142 R 1 is hydrogen, C1-12alkyl, Ar 1 , Ar 2 C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1 -6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC 1-6alkyl, aminoC 1-6alkyl, or a radical of formula -Alkl-C(=O)-R 9 , -Alkl-S(O)-R 9 or -Alkl-S(0)2-R 9 , wherein Alklis 5 C1-6alkanediyl, R 9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl; R 2 , R 3 and R 16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, amino C 1-6alkyloxy, mono- or di(C 1-6alkyl)aminoC 1-6alkyloxy, Arl 1 , Ar 2 C 1-6alkyl, 10 Ar 2 oxy, Ar 2 C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R 2 and R 3 taken together may form a bivalent radical of formula -O-CH2-O- (a-1), 15 -O-CH2-CH2-O- (a-2), -O-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), or -CH=CH-CH=CH- (a-6); 20 R 4 and R 5 each independently are hydrogen, halo, Arl, C1-6alkyl, hydroxy C1-6alkyl, C1-6alkyloxyC-6alkyl , C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, Ci -6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl; R 6 and R 7 each independently are hydrogen, halo, cyano, C1-6alkyl, 25 C1-6alkyloxy, Ar 2 oxy, trihalomethyl, C1-6alkylthio, di(Cl-6alkyl)amino, or when on adjacent positions R 6 and R 7 taken together may form a bivalent radical of formula -O-CH2-O- (c-1), or -CH=CH-CH=CH- (c-2); R 8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, 30 C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC 1-6alkyl, hydroxyC 1-6alkyl, aminoC 1-6alkyl, mono- or di(C 1-6alkyl) aminoC 1-6alkyl, imidazolyl, haloC 1-6alkyl, C 1-6alkyloxyC 1-6alkyl, aminocarbonylC 1-6alkyl, or a-radical-of formula -O-RIO (b-i1), 35 -S-R 10 (b-2), -N-R 1 1R 12 (b-3), 249 WO 2006/135636 PCT/US2006/022142 wherein R 10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar 1 , Ar 2 C1-6alkyl, C 1-6alkyloxycarbonylC 1-6alkyl, a radical or formula -Alk 2 -OR 13 or -Alk 2 -NR 14 R 15 ; R 11 is hydrogen, Cl-12alkyl, Ar 1 or Ar 2 C1-6alkyl; 5 R 12 is hydrogen, C1-6alkyl, Cl-16alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Arl1, Ar 2 C1.6alkyl, C1-6alkylcarbonylC1-6alkyl, a natural amino acid, Arlcarbonyl, Ar 2 C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6 alkylcarbonyl, amino, C1-6alkylamino, 10 C 1-6alkylcarbonylamino, or a radical of formula -Alk 2 -OR 13 or -Alk 2 -NR 14 R 15 ; wherein Alk 2 is Cl-6alkanediyl; R 13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar 1 or Ar 2 C1-6alkyl; R 14 is hydrogen, C1-6alkyl, Ar 1 or Ar 2 C1-6alkyl; R 15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar 1 or Ar 2 C1-6alkyl; R 17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar 1 ; 15 R 18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo; R 19 is hydrogen or C1-6alkyl; Ar 1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo; and Ar 2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, 20 C1-6alkyloxy or halo.

45. The method of claim 44 wherein said farnesyl transferase inhibitor comprises a compound of formula (I) wherein X is oxygen and the dotted line represents a bond. 25

46. The method of claim 44 wherein said farnesyl transferase inhibitor comprises a compound of formula (I) wherein R 1 is hydrogen, C1-6alkyl, C 1-6alkyloxy C1-6alkyl or, mono- or di(C1-6alkyl)aminoC1-6alkyl; R 2 is halo, C1-6alkyl, C2-6alkenyl, C1-6alkyloxy, trihalomethoxy, or hydroxyCl-6alkyloxy; and R 3 is hydrogen. 30

47. The method of claim 44 wherein said farnesyl transferase inhibitor comprises -a-compound-of formula-(-I)-wherein R 8 -is-hydrogen,-hydroxy,-haloC:-6alkyl, hydroxyC 1-6alkyl, cyanoC 1-6alkyl, C 1-6alkyloxycarbonylC 1-6alkyl, imidazolyl, or a radical of formula -NR 11 R 12 wherein R 11 is hydrogen or C1-12alkyl and R 12 is 35 hydrogen, C 1-6alkyl, C 1-6alkyloxy, C 1-6alkyloxyC1-6alkylcarbonyl, hydroxy, or a radical of formula -Alk 2 -OR 13 wherein R 13 is hydrogen or C1-6alkyl. 250 WO 2006/135636 PCT/US2006/022142

48. The method of claim 44 wherein the farnesyl transferase inhibitor is (+)-6 [amino(4-chlorophenyl)( 1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- 1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt 5 thereof.

49. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' wherein Rw and Rx are independently selected from hydrogen, alkyl, alkenyl, aralkyl, or 10 heteroaralkyl, or may optionally be taken together to form a 5 to 7 membered ring, selected from the group consisting of: NC 'N 'N 'N , 0 O S O N(alkyl) 'N 'N NH, and 15

50. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' wherein B is selected from: a nine to ten membered benzo-fused heteroaryl, or, if R 3 is present, phenyl or heteroaryl, provided that B is not thiadiazinyl; and R 3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, 20 nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R4, -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl. 25

51. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' wherein B is selected from: phenyl or heteroaryl, provided that B is not thiadiazinyl; and R 3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, 30 cycloalkyl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , 251 WO 2006/135636 PCT/US2006/022142 alkylamino, heterocyclyl optionally substituted with R4, alkoxyether, -O(cycloalkyl), phenoxy optionally substituted with R 4 , or dialkylamino.

52. The method as defined in any of claims 1-43, wherein said FLT3 kinase 5 inhibitor comprises a compound of Formula P wherein Y is a direct bond, O, NH, or N(alkyl); Ra is alkoxy, heteroaryl optionally substituted with Rs, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with Rs, pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally substituted with Rs, heterocyclyl 10 optionally substituted with Rs, -CONRwRx, -N(Ry)CON(Rw)(Rx), -N(Rw)CORy, -SRy, -SORy, -SO 2 Ry, or -NRwSO 2 Ry; and Rbb is hydrogen, halogen or alkoxy.

53. The method as defined in any of claims 1-43, wherein said FLT3 kinase 15 inhibitor comprises a compound of Formula P wherein Z is NH or CH 2 ; R 1 and R 2 are independently selected from the following: n R a n Ra -- Rbb (a-1), (a-4), or (a-5) 20 wherein n is 1, 2, or 3; Yis O; Ra is alkoxy, hydroxyl, heteroaryl optionally substituted with Rs, alkylamino, dialkylamino, pyrrolidinonyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, -CONRwRx, -N(Ry)CON(Rw)(Rx), -SO 2 Ry, or 25 -NRwSO 2 Ry; Rs is one substituent independently selected from: -C(O)alkyl, -SO 2 alkyl, -C(0)N(alkyl),-alkyl; or--C(l4)alkyl:-ORH, aid R 3 is one substituent independently selected from: alkyl, alkoxy, cycloalkyl, heterocyclyl, -O(cycloalkyl), phenoxy, or dialkylamino. 30 252 WO 2006/135636 PCT/US2006/022142

54. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' wherein q is 1 or 2; Q is NH, O, or a direct bond; 5 X is N; Z is NH; B is selected from: phenyl and pyridinyl; R 1 and R 2 are independently selected from the following: Y YRa -- Rbb 10 (a-1), or (a-5) Ra is alkoxy, hydroxyl, alkylamino, dialkylamino, pyrrolidinonyl optionally substituted with Rs, heterocyclyl optionally substituted with Rs, or -NRwSO 2 Ry; Rbb is hydrogen or alkoxy; and 15 R 3 is one substituent selected from: alkyl, alkoxy, heterocyclyl, -O(cycloalkyl), or dialkylamino.

55. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' selected from the group consisting of: NO H N MeO N 253 WO 2006/135636 PCT/US2006/022142 LII1\/\NH 0 N MeO MeO N H N 0 HOO N HO N / -H NH N N 0 NH MeON N2 254 WO 2006/135636 PCT/US2006/022142 0 NNH H N MeO N MeO N H H N N N N N O-O& 0 H H N N / \N N 0 N NH HH H _ N 0 O N ; and 255 WO 2006/135636 PCT/US2006/022142 0 N -NH H N N /N

56. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' selected from the group consisting of: 0 N NH H (N MeO MeO N H H N N -T N NO 0 256 WO 2006/135636 PCT/US2006/022142 H H N N H 0 N N N O ; and N-NH H N H N NONN 'NN

57. The method as defined in any of claims 1-43, wherein said FLT3 kinase inhibitor comprises a compound of Formula I' wherein 257 WO 2006/135636 PCT/US2006/022142 B Rz Z N RN Formula I and N-oxides, pharmaceutically acceptable salts, and stereochemical isomers thereof, wherein: qis0, 1 or2; 5 pis 0 or 1; Q is NH, N(alkyl), O, or a direct bond; X is N, or C-CN, or CH provided that Rbb is not heteroaryl or halogen; Z is NH, N(alkyl), or CH 2 ; B is selected from: a nine to ten membered benzo-fused heteroaryl, or, if R 3 is 10 present, phenyl or heteroaryl, provided that B is not thiadiazinyl; one of R, and R 2 is H, and the other is independently selected from the following: S¥ Ra / Ra U nRaR /Ra (a-1), (a-2), (a-3), or (a-4) 15 wherein n is 1, 2, 3 or 4; Y is a direct bond, O, S, NH, or N(alkyl); Ra is alkoxy, phenoxy, heteroaryl optionally substituted with R 5 , hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R 5 , pyrrolidinonyl optionally substituted with Rs, piperidinonyl optionally 20 substituted with Rs, cyclic heterodionyl optionally substituted with R 5 , heterocyclyl optionally substituted with Rs, squaryl, -COORy, -CONRwRx, -N(Rw)CON(Ry)(Rx), -N(Ry)CON(Rw)(Rx), -N(Rw)C(O)ORx, -N(Rw)CORy, -SRy, -SORy -SO 2 Ry,---NRwSO 2 Ry, -NRwS-O 2 Rx, -- SO3Ry, -OS-O 2 NRwRx, or -SO2NRwRx; 25 Rs is one, two, or three substituents independently selected from: halogen, cyano, trifluoromethyl, amino, hydroxyl, alkoxy, -C(0)alkyl, -SO 2 alkyl, -C(0)N(alkyl) 2 , alkyl, -C(1- 4 )alkyl-OH, or alkylamino; 258 WO 2006/135636 PCT/US2006/022142 Rw and Rx are independently selected from: hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or R, and Rx may optionally be taken together to form a 5 to 7 membered ring, selected from the group consisting of: N N " 'N, ' ' N , O , L S L N(alkyl) 'N 'N 5 NH, and Ry is selected from: hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, aralkyl, heteroaralkyl, or heteroaryl; and R 3 is one or more substituents independently selected from: alkyl, alkoxy, halogen, nitro, cycloalkyl optionally substituted with R 4 , heteroaryl optionally 10 substituted with R 4 , alkylamino, heterocyclyl optionally substituted with R 4 , alkoxyether, -O(cycloalkyl), pyrrolidinonyl optionally substituted with R 4 , phenoxy optionally substituted with R 4 , -CN, -OCHF 2 , -OCF 3 , -CF 3 , halogenated alkyl, heteroaryloxy optionally substituted with R 4 , dialkylamino, -NHSO 2 alkyl, or -SO 2 alkyl; wherein R 4 is independently selected from: halogen, cyano, 15 trifluoromethyl, amino, hydroxyl, alkoxy, -C(O)alkyl, -CO 2 alkyl, -SO 2 alkyl, -C(O)N(alkyl) 2 , alkyl, or alkylamino.

58. The method of claim 49, wherein the farnesyl transferase inhibitor is (+)-6 20 [amino(4-chlorophenyl)(1-methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

59. The method of claim 50, wherein the farnesyl transferase inhibitor is (+)-6 25 [amino(4-chlorophenyl)(1-methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

60. The method of claim 51, wherein the farnesyl transferase inhibitor is (+)-6 30 [amino(4-chlorophenyl)(1-methyl- 1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- 1 259 WO 2006/135636 PCT/US2006/022142 methyl-2(1IH)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

61. The method of claim 52, wherein the farnesyl transferase inhibitor is (+)-6 5 [amino(4-chlorophenyl)(1-methyl-l1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1 methyl-2(1lH)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

62. The method of claim 53, wherein the farnesyl transferase inhibitor is (+)-6 10 [amino(4-chlorophenyl)(1-methyl-l1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- 1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

63. The method of claim 54, wherein the farnesyl transferase inhibitor is (+)-6 15 [amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

64. The method of claim 55, wherein the farnesyl transferase inhibitor is (+)-6 20 [amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

65. The method of claim 56, wherein the farnesyl transferase inhibitor is (+)-6 25 [amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof.

66.. Tffe-1mfieh6d-f claiiii-57, wfieiefi the far esyftranisferase inhibitor is (+)-6 30 [amino(4-chlorophenyl)(1-methyl- 1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- 1 methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition salt thereof. 260